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Review

Oxidative Stress-Induced Hypertension of Developmental Origins: Preventive Aspects of Antioxidant Therapy

by
You-Lin Tain
1,2 and
Chien-Ning Hsu
3,4,*
1
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
2
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
3
Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
4
School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
*
Author to whom correspondence should be addressed.
Antioxidants 2022, 11(3), 511; https://doi.org/10.3390/antiox11030511
Submission received: 28 January 2022 / Revised: 3 March 2022 / Accepted: 5 March 2022 / Published: 7 March 2022
(This article belongs to the Special Issue Antioxidant Therapy for Management of Oxidative Stress Induced Hypertension)
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Abstract

:
Hypertension remains the leading cause of disease burden worldwide. Hypertension can originate in the early stages of life. A growing body of evidence suggests that oxidative stress, which is characterized as a reactive oxygen species (ROS)/nitric oxide (NO) disequilibrium, has a pivotal role in the hypertension of developmental origins. Results from animal studies support the idea that early-life oxidative stress causes developmental programming in prime blood pressure (BP)-controlled organs such as the brain, kidneys, heart, and blood vessels, leading to hypertension in adult offspring. Conversely, perinatal use of antioxidants can counteract oxidative stress and therefore lower BP. This review discusses the interaction between oxidative stress and developmental programming in hypertension. It will also discuss evidence from animal models, how oxidative stress connects with other core mechanisms, and the potential of antioxidant therapy as a novel preventive strategy to prevent the hypertension of developmental origins.

1. Introduction

Hypertension is the number one risk factor for global deaths, affecting one in three adults across the world [1,2]. Significant interest has recently focused on the fact that the origins of hypertension can begin in early life [3,4,5]. Now this concept, based on observing that the developing fetus being exposed to adverse conditions in utero increases the risk for chronic diseases happening later in life, has been termed as the “developmental origins of health and disease (DOHaD)” [6]. The hypertension of developmental origins can be programmed by a number of modifiable environmental risk factors [7,8,9,10], especially those linked to maternal nutrition. Notably, the DOHaD concept, besides determining the early-life risk for the developmental programming of hypertension, offers a novel way to prevent hypertension by reprogramming therapy [11]. By switching therapy from adulthood to early life prior to illness onset, we have the potential to reverse adverse programming processes that would lead to hypertension. Accordingly, one may assume that early reprogramming therapy serves as an innovative strategy to reduce the burden of hypertension globally.
A growing body of evidence shows that oxidative stress plays a pivotal role in the pathogenesis of hypertension [12,13,14,15]. The overproduction of deleterious reactive oxygen and nitrogen species (ROS and RNS) that overwhelm the cellular antioxidant capacity results in pathogenic oxidative stress [16]. Experimental evidence supports that a ROS/nitric oxide (NO) disequilibrium under oxidative stress favors oxidation reactions involved in major blood pressure (BP)-controlled organs such as the brain, kidneys, heart, and blood vessels, underpinning the development of hypertension [12,13,14,15]. Conversely, treatment with antioxidants has been suggested to lower oxidative stress and therefore BP [16,17].
Although cumulative evidence has shown the impact of oxidative stress and antioxidant therapy in established hypertension [12,13,14,15,16,17,18], less attention has been paid to their implications in the hypertension of developmental origins. Therefore, the purpose of the current review is to highlight the best available evidence on the interaction between oxidative stress and the developmental programming of hypertension. In this review, attempts will be made to discuss the role of oxidative stress in the hypertension of developmental origins, its associations with the core mechanisms of developmental programming behind hypertension, and the potential of antioxidant therapy as a novel preventive strategy for the hypertension of developmental origins.
The PubMed/MEDLINE database was used to identify related peer-reviewed journal articles published in English between January 1980 and December 2021. We used the following search keywords: “antioxidants”, “hypertension”, “blood pressure”, “developmental programming”, “DOHaD”, “free radicals”, “offspring”, “progeny”, “mother”, “prenatal”, “nitric oxide”, “oxidative stress”, “pregnancy”, “reprogramming”, “reactive oxygen species”, “reactive nitrogen species”, and “vitamin”. Additional studies were selected based on references from eligible articles.

2. Oxidative Stress and Hypertension

2.1. ROS/NO Disequilibrium

Oxidative stress has been characterized as a disturbance in the ROS/NO balance, with the notion that ROS and RNS damage biological molecules [16]. Both ROS and RNS collectively constitute free radicals and non-radical reactive species. ROS include free radicals such as superoxide anion (O2−) and hydroxyl anion (OH−) as well as non-radical molecules such as hydrogen peroxide (H2O2). The main enzyme sources for superoxide are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidase, cyclooxygenases, lipoxygenases, and the mitochondrial respiration chain [19]. The superoxide anion radical initiates a cascade of reactions resulting in the generation of other ROS. RNS include peroxynitrite (ONOO-) and its reaction products, such as nitrogen dioxide (NO2). Much of RNS-dependent cytotoxicity resides on peroxynitrite, formed by high levels of NO and superoxide [20]. Conversely, our body has various antioxidants to ameliorate the harmful effects of ROS/RNS. This antioxidant machinery has two arms: (1) enzymatic components consisting of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase, and (2) non-enzymatic antioxidants such as glutathione (GSH) and vitamins [21].
At an optimal level, NO physiologically functions as a gasotransmitter and as a vasodilator. NO is generated via a reaction involving the conversion of l-arginine to l-citrulline by a family of NO synthases (NOSs). There are three isoforms of NOS: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NOS [22]. In the presence of high ADMA levels, NOS isoenzymes become uncoupled to produce peroxynitrite, further contributing to the reduced NO bioavailability and increased oxidative stress [23]. Considering both ROS and NO behave as BP modulators, maintenance of the ROS/NO balance is required for strict BP control.

2.2. Oxidative Stress and Hypertension

The heart, kidneys, brain, and blood vessels are prime organs involved in the regulation of BP. Under physiological conditions, the maintenance of normal BP requires the coordinated interplay of several regulatory players, including the renin–angiotensin system (RAS), natriuretic peptides, sodium excretion, the endothelium, and the sympathetic nervous system [24]. Oxidative stress not only contributes to BP-controlled organ dysfunction and remodeling through oxidative damage but also impairs coordinated regulatory systems, leading to hypertension [12,13,14,15]. Each organ system will be discussed in turn.

2.2.1. Cardiovascular System

Blood pressure can be determined by cardiac output and the resistance of blood vessels. Endothelial cells are important constituents of blood vessels that play key roles in cardiovascular homeostasis [25]. Endothelial dysfunction is characterized by reduced vasodilation, pro-thrombotic settings, and a pro-inflammatory state, which together are implicated in the pathophysiology of hypertension. These events can be mediated by excessive ROS formed by vascular walls [26]. The vasculature is a major source of NADPH-oxidase-derived ROS, which has a vital role in vascular damage under pathological conditions [26]. Additionally, several endothelium-derived vasoconstricting factors, such as angiotensin II (Ang II), endothelin, urotensin II, vasoconstrictor prostaglandins, and thromboxane A2, can be released by endothelial cells and contribute to the vasoconstrictor effects.
Conversely, reduced NO bioavailability, a well-known endothelium-derived relaxing factor, is considered a hallmark of endothelial dysfunction [27]. The eNOS-derived NO is responsible for vasodilation within the endothelium. Loss of l-arginine and cofactor tetrahydrobiopterin (BH4) leads to the uncoupling of eNOS, in which the enzyme produces superoxide anion rather than nitric oxide, further generating peroxynitrite to induce vascular pathogenesis. Likewise, ADMA can uncouple NOS isoenzymes to form superoxide, contributing to endothelial dysfunction [28]. The activation of oxidative stress not only disturbs the balance between vasodilators and vasoconstrictors affecting vascular tone but also ultimately leads to vascular dysfunction, abnormalities of vessels, atherosclerosis, arterial stiffness, and vascular remodeling [29].
Collectively, there is significant evidence indicating that vascular oxidative stress induces vasoconstriction and remodeling of blood vessels, contributing to the development of hypertension [14].

2.2.2. Renal System

Several lines of evidence clearly show that renal oxidative stress is a key factor in the development of hypertension [30]. Increased ROS in the kidneys have been found in various hypertensive models, such as spontaneously hypertensive rat (SHR), stroke-prone SHR, DOCA-salt hypertension rat, Dahl salt-sensitive rat, and 5/6 nephrectomy rat [31,32,33,34,35]. In addition, extracellular SOD knockout mice have been found to display increased renal oxidative stress and develop hypertension [36]. Additionally, knockout of nNOS in macula densa causes the elevation of BP in mice [37]. Increased oxidative stress markers, such as 8-hydroxydeoxyguanosine (8-OHdG) expression in the kidneys, have been reported in various models of established and programmed hypertension, such as SHR [38], Dahl salt-sensitive rat [39], maternal high-fat diet [40], and maternal high-fructose diet [41]. Another line of evidence comes from antioxidant therapy for the management of oxidative-stress-induced hypertension [12,18,42,43,44]. Several antioxidants, such as vitamin E [35], melatonin [45], and N-acetylcysteine [46], have shown a beneficial effect on hypertension coinciding with a reduction in renal oxidative stress.

2.2.3. Central Nervous System

The central nervous system (CNS) controls regional sympathetic outflow to target organs (e.g., heart and kidneys) through the integration of neural signals from autonomic brain networks, input from circulating factors, and reflex influences [15]. Results from human and animal studies reveal that overexcitation of the sympathetic nervous system plays a key role in the pathogenesis of hypertension [15]. Neurons that generate central sympathetic vasomotor outflow reside in the rostral ventrolateral medulla (RVLM) of the brain stem [47]. All ROS- and NO-generating enzymes are present in the RVLM [48]. ROS increase sympathoexcitatory inputs to RVLM neurons, whereas iNOS-derived NO promotes sympathoinhibition [49]. Accordingly, a shift from ROS to NO in the RVLM underpins the succession of increase to decrease in sympathetic vasomotor tone that is responsible for the development of hypertension [48,49].
An ever-growing body of evidence supports that increased brain stem oxidative stress contributes to the generation of hypertension. Increased NADPH-oxidase expression and activity has been demonstrated in the RVLM of SHR [50], while the knockdown of its subunits blunts the enhanced central sympathetic outflow and protects against hypertension [51]. Reduced NO in the RVLM, in conjunction with augmented Ang-II-induced oxidative stress also contributes to sympathoexcitation in hypertension [52]. Conversely, interventions that quench ROS have been reported to reduce brain oxidative stress and prevent neurogenic hypertension. The microinjection of tempol [53], CoQ10 [54], or catalase [55] into the RVLM has been reported to blunt hypertension and inhibit brain oxidative stress.

2.2.4. The Regulatory Hormones

In view of the introduction of renal sympathetic denervation into clinical medicine that has demonstrated marked reductions in BP in patients with resistant hypertension [56], there has been interest in interorgan crosstalk involving various regulatory hormones contributing to hypertension that more closely reflects the human condition [57,58,59]. These regulatory hormones include, but are not limited to, the RAS [59], cytokines [60], norepinephrine [61], atrial natriuretic peptide [61], endothelin [62], urotensin II [63], prostaglandins [57], melatonin [64], cortisol [65], hydrogen sulfide [66], and gut-microbiota-derived metabolites [67].
Together these observations suggest that oxidative stress could be a core mechanism involved in interorgan communication via various regulatory hormones contributing to hypertension. However, although these studies highlight that oxidative stress correlates with established hypertension, its role in the hypertension of developmental origins has received little attention from researchers. A summary of the interaction between maternal insults implicated in oxidative stress and the prime organ system involved in the developmental programming of hypertension is depicted in Figure 1.

3. Oxidative-Stress-Related Hypertension of Developmental Origins

3.1. Oxidative Stress during Pregnancy

Fetal oxygen requirements vary at various stages of pregnancy [68]. During the first trimester, fetal oxygen levels are low. However, increasing oxygen need happens, during the second and third trimesters, for the formation of fetal-placental circulation and the rapid gain of fetal weight [69]. Oxidative damage occurs in a compromised pregnancy owing to the failure of defensive antioxidant mechanisms in responding to excessive ROS and RNS [70]. Many adverse conditions in pregnancy result in increased oxidative stress, including obesity, diabetes, preeclampsia, maternal smoking, and intrauterine growth retardation (IUGR) [71]. Accordingly, oxidative stress adversely affects the developing fetus, resulting in adult disease in later life [10,72].

3.2. Evidence from Human Studies

The association between the hypertension of developmental origins and low birth weight (LBW) was first highlighted by David Barker and colleagues in the late 1980s [73]. Another important observation from the Dutch Hunger Winter Study was that maternal undernutrition has lasting, negative effects on offspring health, including hypertension [74]. Additionally, several mother-child cohorts provide important support for the developmental programming of hypertension. A variety of early-life risks associated with offspring hypertension have been acknowledged, including maternal smoking [75], maternal obesity [76], low vitamin D consumption [77], gestational hypertension [78], IUGR [79], and short-term breastfeeding [80].
Although human observational studies provide relevant evidence correlating early-life factors with the developmental programming of hypertension, the direct cause-and-effect relationships between oxidative stress and offspring hypertension that drive programming processes cannot be established and therefore it is difficult to identify a potential reprogramming strategy.

3.3. Evidence from Animal Studies

In recent years, our understanding of the molecular mechanisms behind the hypertension of developmental origins has grown by using animal models [81,82]. These mechanisms contain oxidative stress, reduced nephron number, aberrant activation of the RAS, dysregulated nutrient-sensing signals, gut microbiota dysbiosis, and so on [9,10,11,81]. Among them, oxidative stress has a crucial role and is closely interconnected to other core mechanisms behind the hypertension of developmental origins.
The present review is limited to adverse early-life insults beginning in pregnancy and lactation, with a focus on the oxidative-stress-related hypertension of developmental origins. Table 1 shows that developmental programming of hypertension is related to oxidative stress in various organ systems, which leads to significant changes in offspring BP [46,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119]. Diverse environmental insults can induce the oxidative-stress-related hypertension of developmental origins. These insults can be grouped into maternal nutritional imbalance [83,84,85,86,87,93,94,95,96,97,100,108,111,112], maternal illness [46,88,92,98,99], pregnancy complications [107,109,110,113,117,118,119], exposure to environmental chemicals [105,106,114], and maternal medication [89,90,91,115,116].
Maternal nutritional insults are the leading causes of the oxidative-stress-related hypertension of developmental origins in animal models. Under- and over-nutrition can both induce nutritional programming [120]. These nutritional risk factors include calorie restriction [83,84,85,86], protein restriction [87], and a diet high in fructose [93,94,95,96], fat [100,108], salt [111,112], or methyl-donors [97]. Another factor interfering with oxidative stress programming is maternal illness. Maternal diabetes [89,90,91], preeclampsia [92], CKD [98,99], and hypertension [109,110] have been reported to induce oxidative stress and the hypertension of developmental origins concurrently. Additionally, pregnancy complications such as reduced uterine perfusion [107], inflammation [113], and hypoxia [117,118,119] are also relevant to oxidative-stress-related programmed hypertension. Offspring hypertension can also be programmed by dams exposed to environmental chemicals, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [105], bisphenol A [106], and di-n-butyl phthalate [114]. Moreover, medication use such as glucocorticoid can program the hypertension of developmental origins [89,90,91,115,116].
Rats are the most commonly used species. Other species such as chicken [118] and sheep [115,116,119] have also been used to evaluate the hypertension of developmental origins. Considering that rats reach sexual maturity at 8–10 weeks of age, and in adulthood each month of the life of a rat is equivalent to 3 human years [121], Table 1 lists the timing of developing hypertension ranging from 8 weeks to 6 months of age in rats, which corresponds to humans from childhood to early adulthood.

3.4. Mechanisms Underpinning Oxidative Stress in Hypertension of Developmental Origins

There are several oxidative-stress-mediated mechanisms involved in the pathogenesis of programmed hypertension, including increased ROS [91,95,110,114,116], increased ROS-producing enzyme expression [86,94,101,107,109,112], decreased antioxidant capabilities [91,100,101,112], an impaired ADMA–NO pathway [83,84,85,88,89,91,92,93,98,99,102,103,104,105,106,116,118,119], increased peroxynitrite [85,90,109,111], and increased oxidative damage [46,83,84,87,90,93,94,96,97,98,99,100,103,104,105,106,107,108,109,112,115,117].
3-nitrotyrosine (3-NT) is a marker of oxidative stress formed due to the nitration of protein-bound and free tyrosine residues by reactive peroxynitrite molecules [122]. Table 1 shows that increased 3-NT in the vessels [85,111], kidneys [90], and brain [109] is associated with the hypertension of developmental origins.
Prior work indicates that ADMA-related NO–ROS imbalance in early life induces adulthood hypertension [123]. Several studies support the notion that ADMA is a key risk factor related to oxidative stress programming in various programming models, such as caloric restriction [83,84], diabetes [89], preeclampsia [92], maternal CKD [98,99], combined dexamethasone and TCDD exposure [105], prenatal bisphenol A exposure and high-fat diet [106], and high-salt diet [111]. NO deficiency in the vessels [85] and kidneys [102] is also relevant to the hypertension of developmental origins.
Several frequently used markers of lipid peroxidation have been used to detect oxidative damage in models of programmed hypertension, including F2-isoprostanes [46,87], thiobarbituric acid reactive substances (TBARS) [90], malondialdehyde (MDA) [94,100,112], and 4-hydroxynonenal (4-NHE) [115]. As shown in Table 1, the hypertension of developmental origins induced by various maternal insults is associated with lipid peroxidation in the kidneys [46,87,113], vessels [90,112], and brain [94]. In addition, 8-hydroxydeoxyguanosine (8-OHdG) is the most frequently detected and studied oxidized nucleoside of DNA [124]. Maternal caloric restriction [83,84], a high-fructose diet [93], a maternal methyl-deficient or donor-rich diet [97], CKD [98,99], prenatal dexamethasone exposure [103,104,105], combined dexamethasone and TCDD exposure [105], prenatal bisphenol A exposure and high-fat diet [106], and high-fat diet [108] have been shown to give rise to programmed hypertension in the presence of increased 8-OHdG expression.
It is noteworthy that most studies have mainly focused on the renal and cardiovascular systems; rather less attention has been paid to oxidative stress programming on other organ systems, including the brain [94,109,115], spleen [95], and adrenal glands [101].

3.5. Oxidative-Stress-Induced Renal Programming

During development, the fetal kidney is susceptible to adverse early-life events, leading to changes in structure and function, namely renal programming [125]. Renal programming is the most commonly studied mechanism behind the hypertension of developmental origins [4,5,11]. A reduced nephron number can develop during pregnancy through childhood to later life in different animal models of renal programming [126]. Maternal insults need only last for 1–2 days to impair nephrogenesis, resulting in a permanent reduction in the nephron number [127]. Accordingly, the main phenotype of renal programming associated with a reduced nephron number is hypertension [126].
An impaired ADMA–NO pathway is tightly linked to oxidative stress in determining renal programming [123]. NO deficiency in pregnancy induced by NOS inhibitor NG-nitro-l-arginine methyl ester (L-NAME) caused renal programming, coinciding with increased oxidative stress in adult offspring [46]. Additionally, maternal NO deficiency was able to modify more than 2000 renal transcripts in a 1-day-old offspring kidney. It has been found that several genes belonging to the RAS and arachidonic acid metabolism pathway contribute to the pathogenesis of programmed hypertension [46]. In a prenatal dexamethasone exposure model [102,127], offspring rats developed hypertension coinciding with a reduced nephron number, increased plasma ADMA levels, and reduced renal NO production. Likewise, the links between oxidative stress and a reduced nephron number have been reported in a caloric restriction model [83] and a streptozotocin-induced diabetes model [89]. Moreover, our prior work has demonstrated that ADMA can impair nephrogenesis [89]. Metanephroi grown in 2 or 10 µM ADMA displayed reduced nephron numbers in a dose-dependent manner [89]. When we treated cultured metanephroi with 10 µM ADMA, the next-generation sequencing (NGS) analysis identified 1221 differential expressed genes [128]. Among them, Ephx2, Avpr1a, Npy1r, Hba2, and Hba-a2, have been linked to programmed hypertension in other models [129,130]. Together, these observations support the notion that oxidative-stress-induced renal programming contributes to the hypertension of developmental origins.

3.6. Oxidative-Stress-Induced Cardiovascular Programming

The fetal cardiovascular system is similar to the developing kidneys with great vulnerability to adverse in utero conditions [131]. Oxidative stress may mediate developmental plasticity in the CV system with structural and functional changes during the organogenesis of the heart–vascular system, leading to endothelial dysfunction, a stiffer vascular tree, fewer cardiomyocytes, and small coronary arteries, through cardiovascular programming [131,132,133]. Table 1 documents several cardiovascular programming models that are relevant to oxidative stress, including maternal caloric restriction [85,86], diabetes [91], high-salt diet [111,112], and prenatal hypoxia exposure [118,119].
In the maternal caloric restriction model, offspring displayed high BP accompanied with a decrease in NOS activity in the microvessels and increased cardiac xanthine-oxidase expression [85,86]. Another study showed that adult offspring born to diabetic dams developed hypertension related to an increased ROS level and decreased SOD expression and NO bioavailability in mesenteric arteries [91]. Moreover, developmental hypoxia has been reported to impair the NO pathway and endothelial function, consequently programming hypertension in the adult offspring of chickens and sheep [118,119]. In rats and mice, cardiovascular maturation continues past birth, becoming completed by the second week postnatally. Unlike rodents, chickens and sheep share similar temporal windows of precocial cardiovascular development and maturation with humans [134]. Therefore, cardiovascular data derived from these two models provide a useful translation to the human situation.
In addition, endothelium-dependent hyperpolarization (EDH), a dominant vasodilator in resistance arteries, is also involved in the regulation of BP. Considering that oxidative stress impairs EDH during hypertension in some vessels [135], reduced EDH might contribute to the oxidative-stress-induced hypertension of developmental origins. Indeed, a previous study has shown that offspring exposed to a high-fat diet display reduced EDH and BP elevation concurrently, despite the mechanisms of oxidative stress remaining undetermined [136].

3.7. Other Mechanisms Related to Oxidative Stress Programming

Considering a wide spectrum of early-life insults create similar outcomes (i.e., hypertension) in adult offspring, it is logical to think that common mechanisms contribute to the hypertension of developmental origins. In addition to oxidative stress, several mechanisms have been proposed, including glucocorticoid effect, aberrant RAS, dysregulated nutrient-sensing signals, gut microbiota dysbiosis, etc. [4,5,10,11,59,81]. Among them, oxidative stress plays a decisive role and is tightly interconnected to other core molecular pathways involved in the hypertension of developmental origins (Figure 2).
First, several studies have linked increased fetal glucocorticoid exposure to the developmental programming of hypertension in adult offspring [101,102,103,104,105,115,116]. One previous study reported that programmed male offspring exhibited reduced antioxidant glutathione peroxidase 1 (Gpx1) expression and increased NADPH-oxidase expression in the adrenal glands [101]. Second, the aberrant activation of the RAS is a well-known mechanism underlying the hypertension of developmental origins [59]. In a maternal hypertension model, offspring hypertension was found to be related to increased expression of angiotensin II type 1 receptor (AT1R) and oxidative-stress-related protein in the brain [109]. Conversely, an early blockade of the RAS by renin inhibitor aliskiren mitigates increases in ADMA and restores NO bioavailability, contributing to the decrease in BP in young spontaneously hypertensive rats (SHRs) [137].
Dysregulated nutrient-sensing signals are also involved in the development of hypertension [132]. In a maternal high-fructose model, the dysfunction of AMP-activated protein kinase (AMPK)-regulated AT1R expression and sirtuin 1 (SIRT1)-mediated mitochondrial biogenesis coincided with increased oxidative stress in RVLM, which in turn increased sympathetic activity and BP in offspring [94]. Besides, a maternal high-fructose diet was found to decrease expression of AMPK, SIRT4, and peroxisome proliferator-activated receptors (PPARs) in offspring kidneys [96].
Furthermore, recent evidence indicates that early development of the gut microbiota influences the development of hypertension [138,139]. Data from several animal models indicate that the interactions between gut microbiota dysbiosis and oxidative stress may contribute to the pathogenesis of programmed hypertension, such as maternal CKD [98], high-fructose diet [96], and high-fat diet [140] models.

4. Antioxidants as Reprogramming Strategies

Concerning our advanced understanding of the DOHaD concept, it turns out that a therapeutic approach can be started earlier, even before hypertension occurs, by so-called reprogramming [11]. In view of the fact that oxidative stress plays a critical role in the hypertension of developmental origins, it is reasonable to assume that antioxidant therapy would be an appropriate reprogramming strategy to protect offspring against programmed hypertension. This section discusses the reprogramming role of natural and synthetic antioxidants that have demonstrated an ability to participate in the main redox reactions and prevent the hypertension of developmental origins.
There are two groups of antioxidants: enzymatic and non-enzymatic antioxidants [141]. Non-enzymatic antioxidants are classified as natural and synthetic antioxidants [142], which could be endogenous and exogenous. Examples of natural non-enzymatic antioxidants are glutathione, carotenoids, flavonoids, polyphenols, and vitamins A, C, and E [141]. A variety of plant materials are known to be sources of natural non-enzymatic antioxidants, such as vegetables, seeds, nuts, and fruits. As reviewed elsewhere [43], several natural antioxidants such as amino acids, vitamins, melatonin, and resveratrol have shown benefits for the prevention of developmental hypertension. Apart from natural antioxidants, several synthetic antioxidants have also been implemented in animal models of programmed hypertension. The potential antioxidants used as reprogramming therapies for the hypertension of developmental origins are illustrated in Figure 3. Each antioxidant will be discussed in turn.

4.1. Vitamins

Two of the most commonly used antioxidants are vitamins C and E. Vitamin C is a potent water-soluble antioxidant, possessing an ability to quench ROS. Vitamin E is a lipid-soluble antioxidant, which can inhibit NADPH oxidase, cyclooxygenase, and lipoxygenase [143]. Perinatal use of vitamin C or E, alone or combined with other antioxidants, has been shown to prevent the development of hypertension in later life [144,145,146]. To date, two studies have showed that maternal vitamin C or E supplementation prevented hypertension programmed by prenatal hypoxia in adult sheep or by maternal inflammation in adult rats, respectively [113,119].

4.2. Amino Acids

l-arginine is the substrate of NOS isoenzymes and l-citrulline is the main precursor of l-arginine [147]. Considering NO deficiency is a core pathogenetic mechanism behind hypertension of developmental origins, these two amino acids have been studied to ameliorate offspring hypertension in later life [102,103,104].
Although perinatal supplementation of l-arginine has shown benefits on intrauterine growth retardation in various models of developmental programming [148], whether the use of l-arginine in pregnancy will also help prevent the hypertension of developmental origins awaits further elucidation. l-arginine can be converted from l-citrulline in the kidneys [149]. Oral l-citrulline supplementation has been used to enhance l-arginine production and bypass hepatic metabolism to raise NO levels [149]. So far, maternal l-citrulline supplementation has been reported to protect adult rat offspring against oxidative stress programming, including in models of maternal caloric restriction [83], streptozotocin-induced diabetes [89], and prenatal dexamethasone exposure [102].
Although there are other amino acids (e.g., l-taurine and l-cysteine) showing reprogramming potentials for the hypertension of developmental origins [9], the relationships between their beneficial effects and oxidative stress remain largely unclear.

4.3. Polyphenols

Polyphenols are the widespread phytochemical antioxidants in food [150]. Studies have demonstrated the valuable effect of polyphenols in the control of oxidative stress by acting as free radical scavengers, stimulators of antioxidant enzymes, NOS activators, and metal chelators [150,151]. Accordingly, polyphenols enhanced vascular endothelial function, resulting in antihypertensive effects [152].
Resveratrol is a commonly used polyphenol as a nutritional supplement [153]. One of the most important ways in which resveratrol reduces ROS levels is via inhibiting NADPH oxidase [154]. Additionally, resveratrol is able to augment NOS expression, increase glutathione level, and enhance expression of antioxidant enzymes [154]. In SHRs, perinatal resveratrol supplementation mitigated the development of hypertension accompanying the improvement of NO bioavailability [155].
Several rat models of oxidative stress programming, such as maternal ADMA administration [88], high-fructose diet [96], adenine-induced CKD [99], or combined dexamethasone and TCDD exposure [105], have been used to assess the reprogramming effects of resveratrol on offspring hypertension. In a maternal CKD model, perinatal resveratrol therapy benefits on offspring’s hypertension coincided with a reduction in renal 8-OHdG expression and an increase in NO bioavailability [99]. Likewise, perinatal resveratrol therapy was found to protect combined TCDD and dexamethasone-exposure-induced hypertension in adult rat offspring and was associated with reduced renal 8-OHdG expression, decreased ADMA levels, and enhanced NO bioavailability [105]. Of note is that the protective effects of resveratrol are also associated with its prebiotic actions to alter gut microbiota [96,99]. These findings support the links between gut microbiota dysbiosis and oxidative stress that underpin the hypertension of developmental origins.
Although resveratrol has shown beneficial effects in programmed hypertension models related to renal programming [88,96,99,105], little is known regarding its reprogramming effects in the brain, heart, and vessels. Surprisingly, the reprogramming effects of other polyphenols have not yet been explored in the hypertension models of developmental origins.

4.4. Melatonin

As a naturally occurring antioxidant, melatonin and its metabolites can scavenge ROS/RNS, enhance expression of antioxidant enzymes, reduce ADMA, and increase NO bioavailability [156,157]. Early-life melatonin treatment has been considered as a reprogramming strategy for many DOHaD-related diseases, including the hypertension of developmental origins [157].
Melatonin treatment in pregnancy and lactation has shown benefits for hypertension in several models of oxidative stress programming, such as maternal l-NAME exposure [46], maternal caloric restriction [84], a maternal methyl-donor-rich diet [97], and a high-fructose diet [130]. The perinatal use of melatonin has been shown to have beneficial effects via the restoration of the NO–ROS balance in a maternal caloric restriction model [84] and a high-fructose model [130]. Additionally, the protective effect of melatonin therapy accompanies diminished lipid peroxidation [46], decreased ADMA concentrations [84], reduced 8-OHdG expression [84,97], and increased NO bioavailability [84,130]. In addition to its antioxidant properties, melatonin has pleiotropically biological functions. Accordingly, the extent that the antioxidant effects of melatonin contribute to its reprogramming benefits against the hypertension of developmental origins is still ambiguous.

4.5. Synthetic Antioxidants

Apart from natural antioxidants, certain synthetic antioxidants have been implemented in animal models of oxidative stress programming to study the hypertension of developmental origins. N-acetylcysteine (NAC), a well-known thiol-containing antioxidant, has been applied in treating disorders associated with oxidative stress [158]; it works not only as a glutathione precursor but also a stable l-cysteine analog for H2S synthesis [158]. A significant decrease in high BP was achieved with perinatal NAC therapy in several models of oxidative stress programming, such as maternal l-NAME administration [46], maternal suramin administration [92], and dexamethasone combined with a postnatal high-fat diet [103]. The beneficial effects of NAC against offspring hypertension are related to reducing lipid peroxidation [46], increasing the glutathione level [103], decreasing renal 8-OHdG expression [103], and enhancing NO production [92].
One study reported that maternal lazaroid therapy, an inhibitor of lipid peroxidation [159], prevented hypertension in adult rat offspring born to dams receiving a protein restriction diet [87]. Another synthetic antioxidant is nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activator dimethyl fumarate (DMF). Considering Nrf2 is a redox-sensing transcription factor that controls numerous genes that are involved in the management of oxidative stress [160], DMF has been used to prevent the hypertension of developmental origins in a combined dexamethasone and high-fat exposure model [104]. Notably, certain synthetic antioxidants (e.g., tempol) have been studied extensively in animal models of oxidative stress [17,161]. Nevertheless, no study has scientifically examined their ability of protecting adult progeny against hypertension programmed by oxidative stress.
As reviewed elsewhere [22,23,123], a number of currently used drugs have been reported to restore the NO–ROS balance via lowering ADMA levels. Telmisartan, rosuvastatin, glucagon-like peptide-1 receptor agonist, and epigallocatechin-3-gallate are able to reduce ADMA levels via decreased expression of the ADMA-generating enzyme. On the other hand, telmisartan, metformin, salvianolic acid A, oxymatrine, atorvastatin, and rosuvastatin can enhance the activity and/or expression of ADMA-metabolizing enzymes and thereby reduce ADMA levels [22,23]. Among them, only metformin has been tested and shown benefits against hypertension, coinciding with its ADMA-lowering action in a maternal high-fructose and post-weaning high-fat diet model [41].

5. Concluding Remarks and Perspectives

There is considerable evidence supporting the idea that oxidative stress is involved in the hypertension of developmental origins and that antioxidant therapy is a potential preventive strategy. However, there are still some unsolved aspects toward clinical translation. Considering promising data from animal studies, it seems logical to think that antioxidant therapy is a potential reprogramming strategy for the oxidative-stress-induced hypertension of developmental origins. Nevertheless, results in humans are still not conclusive, as antioxidant therapy cannot control the global rise of hypertension [12].
Another important aspect is that excessive antioxidant supplementation can turn oxidative stress into a reverse state, namely antioxidant stress [162]. As oxidative stress is not routinely detectable in clinical practice, oxidative stress should be monitored, and perinatal antioxidant therapy should only be used for indicated cases.
Aside from oxidative stress, the hypertension of developmental origins is associated with other core mechanisms [4,5,10,11,59,81]. The protective effects of perinatal antioxidant therapy might also be attributed to the activation of nutrient-sensing signals, rebalancing of the RAS, and altering gut microbiota. Indeed, early interventions targeting other mechanisms (e.g., AMPK activator or RAS blocker) in pregnancy have been shown to prevent progeny against the hypertension of developmental origins [59,163]. Therefore, major advances are needed in our mechanistic understanding of how oxidative stress communicates with other core mechanisms in various organs during different stages of development.
In conclusion, oxidative stress contributes significantly to the hypertension of developmental origins. Antioxidant therapy can serve as a reprogramming strategy to prevent hypertension while awaiting clinical translation. Since the hypertension of developmental origins can be reversible, the knowledge of oxidative stress programming could aid in developing ideal antioxidants as reprogramming therapies toward reducing the global burden of hypertension.

Author Contributions

Conceptualization, Y.-L.T. and C.-N.H.; funding acquisition, Y.-L.T. and C.-N.H.; project administration, Y.-L.T. and C.-N.H.; data curation, C.-N.H. and Y.-L.T.; writing—original draft, C.-N.H. and Y.-L.T.; writing—review and editing, C.-N.H. and Y.-L.T. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Ministry of Science and Technology, Taiwan, grants MOST 110-2314-B-182-020-MY3 (Y.-L.T.) and MOST 110-2314-B-182A-029 (C.-N.H.), and Chang Gung Memorial Hospital, Kaohsiung, Taiwan, grants CORPG8M0201, CORPG8M0151, and CORPG8M0081.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. World Health Organization. Hypertension. 2019. Available online: https://www.who.int/news-room/fact-sheets/detail/hypertension (accessed on 10 January 2022).
  2. Bromfield, S.; Muntner, P. High blood pressure: The leading global burden of disease risk factor and the need for worldwide prevention programs. Curr. Hypertens. Rep. 2013, 15, 134–136. [Google Scholar] [CrossRef] [PubMed]
  3. Ojeda, N.B.; Grigore, D.; Alexander, B.T. Developmental programming of hypertension: Insight from animal models of nutritional manipulation. Hypertension 2008, 52, 44–50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Chong, E.; Yosypiv, I.V. Developmental programming of hypertension and kidney disease. Int. J. Nephrol. 2012, 2012, 760580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Paixão, A.D.; Alexander, B.T. How the kidney is impacted by the perinatal maternal environment to develop hypertension. Biol. Reprod. 2013, 89, 144. [Google Scholar] [CrossRef] [PubMed]
  6. Hanson, M. The birth and future health of DOHaD. J. Dev. Orig. Health Dis. 2015, 6, 434–437. [Google Scholar] [CrossRef]
  7. Hsu, C.N.; Tain, Y.L. The double-edged sword effects of maternal nutrition in the developmental programming of hypertension. Nutrients 2018, 10, 1917. [Google Scholar] [CrossRef] [Green Version]
  8. Guarner-Lans, V.; Ramírez-Higuera, A.; Rubio-Ruiz, M.E.; Castrejón-Téllez, V.; Soto, M.E.; Pérez-Torres, I. Early Programming of Adult Systemic Essential Hypertension. Int. J. Mol. Sci. 2020, 21, 1203. [Google Scholar] [CrossRef] [Green Version]
  9. Hsu, C.N.; Tain, Y.L. Amino Acids and Developmental Origins of Hypertension. Nutrients 2020, 12, 1763. [Google Scholar] [CrossRef]
  10. Dasinger, J.H.; Davis, G.K.; Newsome, A.D.; Alexander, B.T. Developmental Programming of Hypertension: Physiological Mechanisms. Hypertension 2016, 68, 826–831. [Google Scholar] [CrossRef]
  11. Tain, Y.L.; Joles, J.A. Reprogramming: A Preventive Strategy in Hypertension Focusing on the Kidney. Int. J. Mol. Sci. 2015, 17, 23. [Google Scholar] [CrossRef] [Green Version]
  12. Sinha, N.; Dabla, P.K. Oxidative stress and antioxidants in hypertension-a current review. Curr. Hypertens. Rev. 2015, 11, 132–142. [Google Scholar] [CrossRef] [PubMed]
  13. Palm, F.; Nordquist, L. Renal oxidative stress, oxygenation, and hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011, 301, R1229–R1241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Touyz, R.M. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: What is the clinical significance? Hypertension 2004, 44, 248–252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Hurr, C.; Young, C.N. Neural Control of Non-vasomotor Organs in Hypertension. Curr. Hypertens. Rep. 2016, 18, 30. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Sies, H. Oxidative stress: A concept in redox biology and medicine. Redox Biol. 2015, 4, 180–183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Ahmad, K.A.; Yuan Yuan, D.; Nawaz, W.; Ze, H.; Zhuo, C.X.; Talal, B.; Taleb, A.; Mais, E.; Qilong, D. Antioxidant therapy for management of oxidative stress induced hypertension. Free Radic. Res. 2017, 51, 428–438. [Google Scholar] [CrossRef] [PubMed]
  18. Kizhakekuttu, T.J.; Widlansky, M.E. Natural antioxidants and hypertension: Promise and challenges. Cardiovasc. Ther. 2010, 28, e20–e32. [Google Scholar] [CrossRef]
  19. Wilcox, C.S. Reactive oxygen species: Roles in blood pressure and kidney function. Curr. Hypertens. Rep. 2002, 4, 160–166. [Google Scholar] [CrossRef]
  20. Radi, R. Peroxynitrite, a stealthy biological oxidant. J. Biol. Chem. 2013, 288, 26464–26472. [Google Scholar] [CrossRef] [Green Version]
  21. Vertuani, S.; Angusti, A.; Manfredini, S. The antioxidants and pro-antioxidants network: An overview. Curr. Pharm. Des. 2004, 10, 1677–1694. [Google Scholar] [CrossRef] [Green Version]
  22. Tain, Y.L.; Hsu, C.N. Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA). Toxins 2017, 9, 92. [Google Scholar] [CrossRef] [Green Version]
  23. Tain, Y.L.; Hsu, C.N. Targeting on Asymmetric Dimethylarginine-Related Nitric Oxide-Reactive Oxygen Species Imbalance to Reprogram the Development of Hypertension. Int. J. Mol. Sci. 2016, 17, 2020. [Google Scholar] [CrossRef] [Green Version]
  24. Oparil, S.; Acelajado, M.C.; Bakris, G.L.; Berlowitz, D.R.; Cífková, R.; Dominiczak, A.F.; Grassi, G.; Jordan, J.; Poulter, N.R.; Rodgers, A.; et al. Hypertension. Nat. Rev. Dis. Primers 2018, 4, 18014. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Konukoglu, D.; Uzun, H. Endothelial Dysfunction and Hypertension. Adv. Exp. Med. Biol. 2017, 956, 511–540. [Google Scholar] [PubMed]
  26. Bengtsson, S.H.; Gulluyan, L.M.; Dusting, G.J.; Drummond, G.R. Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology. Clin. Exp. Pharmacol. Physiol. 2003, 30, 849–854. [Google Scholar] [CrossRef] [PubMed]
  27. Li, Q.; Youn, J.Y.; Cai, H. Mechanisms and consequences of endothelial nitric oxide synthase dysfunction in hypertension. J. Hypertens. 2015, 33, 1128–1136. [Google Scholar] [CrossRef] [Green Version]
  28. Cardounel, A.J.; Cui, H.; Samouilov, A.; Johnson, W.; Kearns, P.; Tsai, A.L.; Berka, V.; Zweier, J.L. Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J. Biol. Chem. 2007, 282, 879–887. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Sena, C.M.; Leandro, A.; Azul, L.; Seiça, R.; Perry, G. Vascular Oxidative Stress: Impact and Therapeutic Approaches. Front. Physiol. 2018, 9, 1668. [Google Scholar] [CrossRef] [Green Version]
  30. Wilcox, C.S. Oxidative stress and nitric oxide deficiency in the kidney: A critical link to hypertension? Am. J.Physiol. Regul. Integr. Comp. Physiol. 2005, 289, R913–R935. [Google Scholar] [CrossRef]
  31. Tain, Y.L.; Hsu, C.N.; Huang, L.T.; Lau, Y.T. Apocynin attenuates oxidative stress and hypertension in young spontaneously hypertensive rats independent of ADMA/NO pathway. Free Radic. Res. 2012, 46, 68–76. [Google Scholar] [CrossRef]
  32. Chen, X.; Touyz, R.M.; Park, J.B.; Schiffrin, E.L. Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension 2001, 38, 606–611. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Erdely, A.; Freshour, G.; Tain, Y.L.; Engels, K.; Baylis, C. DOCA/NaCl-induced chronic kidney disease: A comparison of renal nitric oxide production in resistant and susceptible rat strains. Am. J. Physiol. Renal Physiol. 2007, 292, F192–F196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Meng, S.; Roberts, L.J.; Cason, G.W.; Curry, T.S.; Manning, R.D., Jr. Superoxide dismutase and oxidative stress in Dahl salt-sensitive and -resistant rats. Am. J. Physiol. 2002, 283, R732–R738. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Tain, Y.L.; Freshour, G.; Dikalova, A.; Griendling, K.; Baylis, C. Vitamin E reduces glomerulosclerosis, restores renal neuronal NOS, and suppresses oxidative stress in the 5/6 nephrectomized rat. Am. J. Physiol. Renal Physiol. 2007, 292, F1404–F1410. [Google Scholar] [CrossRef] [PubMed]
  36. Welch, W.J.; Chabrashvili, T.; Solis, G.; Chen, Y.; Gill, P.S.; Aslam, S.; Wang, X.; Ji, H.; Sandberg, K.; Jose, P.; et al. Role of extracellular superoxide dismutase in the mouse angiotensin slow pressor response. Hypertension 2006, 48, 934–941. [Google Scholar] [CrossRef] [Green Version]
  37. Zhang, J.; Wang, X.; Cui, Y.; Jiang, S.; Wei, J.; Chan, J.; Thalakola, A.; Le, T.; Xu, L.; Zhao, L.; et al. Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice. Hypertension 2021, 78, 1760–1770. [Google Scholar] [CrossRef]
  38. Tain, Y.L.; Huang, L.T.; Lin, I.C.; Lau, Y.T.; Lin, C.Y. Melatonin prevents hypertension and increased asymmetric dimethylarginine in young spontaneous hypertensive rats. J Pineal Res. 2010, 49, 390–398. [Google Scholar] [CrossRef]
  39. Hisaki, R.; Fujita, H.; Saito, F.; Kushiro, T. Tempol attenuates the development of hypertensive renal injury in Dahl salt-sensitive rats. Am. J. Hypertens. 2005, 18, 707–713. [Google Scholar] [CrossRef] [Green Version]
  40. Tain, Y.L.; Lin, Y.J.; Sheen, J.M.; Yu, H.R.; Tiao, M.M.; Chen, C.C.; Tsai, C.C.; Huang, L.T.; Hsu, C.N. High fat diets sex-specifically affect the renal transcriptome and program obesity, kidney injury, and hypertension in the offspring. Nutrients 2017, 9, 357. [Google Scholar] [CrossRef] [Green Version]
  41. Tain, Y.L.; Wu, K.L.H.; Lee, W.C.; Leu, S.; Chan, J.Y.H. Prenatal Metformin Therapy Attenuates Hypertension of Developmental Origin in Male Adult Offspring Exposed to Maternal High-Fructose and Post-Weaning High-Fat Diets. Int. J. Mol. Sci. 2018, 19, 1066. [Google Scholar] [CrossRef] [Green Version]
  42. Siti, H.N.; Kamisah, Y.; Kamsiah, J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul. Pharmacol. 2015, 71, 40–56. [Google Scholar] [CrossRef] [PubMed]
  43. Hsu, C.N.; Tain, Y.L. Early Origins of Hypertension: Should Prevention Start Before Birth Using Natural Antioxidants? Antioxidants 2020, 9, 1034. [Google Scholar] [CrossRef] [PubMed]
  44. Manning, R.D., Jr.; Tian, N.; Meng, S. Oxidative stress and antioxidant treatment invhypertension and the associated renal damage. Am. J. Nephrol. 2005, 25, 311–317. [Google Scholar] [CrossRef] [PubMed]
  45. Tain, Y.L.; Lin, Y.J.; Chan, J.Y.H.; Lee, C.T.; Hsu, C.N. Maternal melatonin or agomelatine therapy prevents programmed hypertension in male offspring of mother exposed to continuous light. Biol. Reprod. 2017, 97, 636–643. [Google Scholar] [CrossRef]
  46. Tain, Y.L.; Lee, C.T.; Chan, J.Y.; Hsu, C.N. Maternal melatonin or N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and renal transcriptome to prevent prenatal N(G)-Nitro-l-arginine-methyl ester (L-NAME)-induced fetal programming of hypertension in adult male offspring. Am. J. Obstet. Gynecol. 2016, 215, 636. [Google Scholar] [CrossRef]
  47. Aicher, S.A.; Milner, T.A.; Pickel, V.M.; Reis, D.J. Anatomical substrates for baroreflex sympathoinhibition in the rat. Brain Res. Bull. 2000, 51, 107–110. [Google Scholar] [CrossRef]
  48. Chan, S.H.; Chan, J.Y. Brain stem NOS and ROS in neural mechanisms of hypertension. Antioxid. Redox Signal. 2014, 20, 146–163. [Google Scholar] [CrossRef]
  49. Chan, J.Y.H.; Chan, S.H.H. Differential impacts of brain stem oxidative stress and nitrosative stress on sympathetic vasomotor tone. Pharmacol. Ther. 2019, 201, 120–136. [Google Scholar] [CrossRef]
  50. Kishi, T.; Hirooka, Y.; Konno, S.; Sunagawa, K. Sympathoinhibition induced by centrally administered atorvastatin is associated with alteration of NAD(P)H and Mn superoxide dismutase activity in rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 2010, 55, 184–190. [Google Scholar] [CrossRef]
  51. Chan, S.H.H.; Wu, C.A.; Wu, K.L.H.; Ho, Y.H.; Chang, A.Y.W.; Chan, J.Y.H. Transcriptional upregulation of mitochondrial uncoupling protein 2 protects against oxidative stress-associated neurogenic hypertension. Circ. Res. 2009, 105, 886–896. [Google Scholar] [CrossRef] [Green Version]
  52. Zanzinger, J. Mechanisms of action of nitric oxide in the brain stem: Role of oxidative stress. Auton. Neurosci. 2002, 98, 24–27. [Google Scholar] [CrossRef]
  53. Li, P.; Zhang, F.; Zhou, Y.B.; Cui, B.P.; Han, Y. Superoxide anions modulate the effects of angiotensin-(1–7) in the rostral ventrolateral medulla on cardiac sympathetic afferent reflex and sympathetic activity in rats. Neuroscience 2012, 223, 388–398. [Google Scholar] [CrossRef] [PubMed]
  54. Chan, S.H.H.; Wu, K.L.H.; Chang, A.Y.W.; Tai, M.H.; Chan, J.Y.H. Oxidative impairment of mitochondrial electron transport chain complexes in rostral ventrolateral medulla contributes to neurogenic hypertension. Hypertension 2009, 53, 217–227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Chan, S.H.H.; Tai, M.H.; Li, C.Y.; Chan, J.Y.H. Reduction in molecular synthesis or enzyme activity of superoxide dismutases and catalase contributes to oxidative stress and neurogenic hypertension in spontaneously hypertensive rats. Free Radic. Biol. Med. 2006, 40, 2028–2039. [Google Scholar] [CrossRef] [PubMed]
  56. Schlaich, M.P.; Sobotka, P.A.; Krum, H.; Lambert, E.; Esler, M.D. Renal sympathetic-nerve ablation for uncontrolled hypertension. N. Engl. J. Med. 2009, 361, 932–934. [Google Scholar] [CrossRef] [PubMed]
  57. Rodrigo, R.; González, J.; Paoletto, F. The role of oxidative stress in the pathophysiology of hypertension. Hypertens. Res. 2011, 34, 431–440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Sata, Y.; Head, G.A.; Denton, K.; May, C.N.; Schlaich, M.P. Role of the Sympathetic Nervous System and Its Modulation in Renal Hypertension. Front. Med. (Lausanne) 2018, 5, 82. [Google Scholar] [CrossRef] [Green Version]
  59. Hsu, C.N.; Tain, Y.L. Targeting the Renin-Angiotensin-Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins. Int. J. Mol. Sci. 2021, 22, 2298. [Google Scholar] [CrossRef]
  60. Harrison, D.G. The immune system in hypertension. Trans. Am. Clin. Climatol. Assoc. 2014, 125, 130–138. [Google Scholar]
  61. Oparil, S.; Chen, Y.F.; Peng, N.; Wyss, J.M. Anterior hypothalamic norepinephrine, atrial natriuretic peptide, and hypertension. Front. Neuroendocrinol. 1996, 17, 212–246. [Google Scholar] [CrossRef]
  62. Rautureau, Y.; Schiffrin, E.L. Endothelin in hypertension: An update. Curr. Opin. Nephrol. Hypertens. 2012, 21, 128–136. [Google Scholar] [CrossRef] [PubMed]
  63. Brito, R.; Castillo, G.; González, J.; Valls, N.; Rodrigo, R. Oxidative stress in hypertension: Mechanisms and therapeutic opportunities. Exp. Clin. Endocrinol. Diabetes 2015, 123, 325–335. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Baltatu, O.C.; Amaral, F.G.; Campos, L.A.; Cipolla-Neto, J. Melatonin, mitochondria and hypertension. Cell Mol. Life Sci. 2017, 74, 3955–3964. [Google Scholar] [CrossRef] [PubMed]
  65. Kelly, J.J.; Mangos, G.; Williamson, P.M.; Whitworth, J.A. Cortisol and hypertension. Clin. Exp. Pharmacol. Physiol. Suppl. 1998, 25, S51–S56. [Google Scholar] [CrossRef] [PubMed]
  66. Hsu, C.N.; Tain, Y.L. Hydrogen Sulfide in Hypertension and Kidney Disease of Developmental Origins. Int. J. Mol. Sci. 2018, 19, 1438. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Khodor, S.A.; Reichert, B.; Shatat, I.F. The microbiome and blood pressure: Can microbes regulate our blood pressure? Front. Pediatr. 2017, 5, 138. [Google Scholar] [CrossRef]
  68. Dennery, P.A. Oxidative stress in development: Nature or nurture? Free Radic. Biol. Med. 2010, 49, 1147–1151. [Google Scholar] [CrossRef]
  69. Carter, A.M. Placental oxygen consumption. Part I. In vivo studies—A review. Placenta 2000, 21, S31–S37. [Google Scholar] [CrossRef]
  70. Jenkins, C.; Wilson, R.; Roberts, J.; Miller, H.; McKillop, J.H.; Walker, J.J. Antioxidants: Their role in pregnancy and miscarriage. Antioxid. Redox Signal. 2000, 2, 623–628. [Google Scholar] [CrossRef]
  71. Thompson, L.P.; Al-Hasan, Y. Impact of oxidative stress in fetal programming. J. Pregnancy 2012, 2012, 582748. [Google Scholar] [CrossRef]
  72. Hsu, C.N.; Tain, Y.L. Developmental Origins of Kidney Disease: Why Oxidative Stress Matters? Antioxidants 2020, 10, 33. [Google Scholar] [CrossRef] [PubMed]
  73. Barker, D.J.; Osmond, C.; Golding, J.; Kuh, D.; Wadsworth, M.E. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989, 298, 564–567. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Painter, R.C.; Roseboom, T.J.; Bleker, O.P. Prenatal exposure to the Dutch famine and disease in later life: An overview. Reprod. Toxicol. 2005, 20, 345–352. [Google Scholar] [CrossRef] [PubMed]
  75. Oken, E.; Huh, S.Y.; Taveras, E.M.; Rich-Edwards, J.W.; Gillman, M.W. Associations of maternal prenatal smoking with child adiposity and blood pressure. Obes. Res. 2005, 13, 2021–2028. [Google Scholar] [CrossRef] [Green Version]
  76. Filler, G.; Yasin, A.; Kesarwani, P.; Garg, A.X.; Lindsay, R.; Sharma, A.P. Big mother or small baby: Which predicts hypertension? J. Clin. Hypertens. 2011, 13, 35–41. [Google Scholar] [CrossRef]
  77. Hrudey, E.J.; Reynolds, R.M.; Oostvogels, A.J.; Brouwer, I.A.; Vrijkotte, T.G. The association between maternal 25-hydroxyvitamin D concentration during gestation and early childhood cardio-metabolic outcomes: Is there interaction with pre-pregnancy BMI? PLoS ONE 2015, 10, e0133313. [Google Scholar] [CrossRef]
  78. Fraser, A.; Nelson, S.M.; Macdonald-Wallis, C.; Sattar, N.; Lawlor, D.A. Hypertensive disorders of pregnancy and cardiometabolic health in adolescent offspring. Hypertension 2013, 62, 614–620. [Google Scholar] [CrossRef] [Green Version]
  79. Keijzer-Veen, M.G.; Finken, M.J.; Nauta, J.; Dekker, F.W.; Hille, E.T.; Frölich, M.; Wit, J.M.; van der Heijden, A.J. Dutch POPS-19 collaborative study group. Is blood pressure increased 19 years after intrauterine growth restriction and preterm birth? A prospective follow-up study in The Netherlands. Pediatrics 2005, 116, 725–731. [Google Scholar] [CrossRef]
  80. Hosaka, M.; Asayama, K.; Staessen, J.A.; Ohkubo, T.; Hayashi, K.; Tatsuta, N.; Kurokawa, N.; Satoh, M.; Hashimoto, T.; Hirose, T.; et al. Breastfeeding leads to lower blood pressure in 7-year-old Japanese children: Tohoku study of child development. Hypertens. Res. 2013, 36, 117–122. [Google Scholar] [CrossRef] [Green Version]
  81. Hsu, C.N.; Tain, Y.L. Animal Models for DOHaD Research: Focus on Hypertension of Developmental Origins. Biomedicines 2021, 9, 623. [Google Scholar] [CrossRef]
  82. McMullen, S.; Mostyn, A. Animal models for the study of the developmental origins of health and disease. Proc. Nutr. Soc. 2009, 68, 306–320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Tain, Y.L.; Hsieh, C.S.; Lin, I.C.; Chen, C.C.; Sheen, J.M.; Huang, L.T. Effects of maternal l-citrulline supplementation on renal function and blood pressure in offspring exposed to maternal caloric restriction: The impact of nitric oxide pathway. Nitric Oxide 2010, 23, 34–41. [Google Scholar] [CrossRef] [PubMed]
  84. Tain, Y.L.; Huang, L.T.; Hsu, C.N.; Lee, C.T. Melatonin therapy prevents programmed hypertension and nitric oxide deficiency in offspring exposed to maternal caloric restriction. Oxid. Med. Cell Longev. 2014, 2014, 283180. [Google Scholar] [CrossRef] [PubMed]
  85. Franco Mdo, C.; Fortes, Z.B.; Akamine, E.H.; Kawamoto, E.M.; Scavone, C.; de Britto, L.R.; Muscara, M.N.; Teixeira, S.A.; Tostes, R.C.; Carvalho, M.H.; et al. Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats. J. Physiol. 2004, 558, 239–248. [Google Scholar] [CrossRef]
  86. Rodríguez-Rodríguez, P.; López de Pablo, A.L.; García-Prieto, C.F.; Somoza, B.; Quintana-Villamandos, B.; Gómez de Diego, J.J.; Gutierrez-Arzapalo, P.Y.; Ramiro-Cortijo, D.; González, M.C.; Arribas, S.M. Long term effects of fetal undernutrition on rat heart. Role of hypertension and oxidative stress. PLoS ONE 2017, 12, e0171544. [Google Scholar] [CrossRef]
  87. Cambonie, G.; Comte, B.; Yzydorczyk, C.; Ntimbane, T.; Germain, N.; Lê, N.L.; Pladys, P.; Gauthier, C.; Lahaie, I.; Abran, D.; et al. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 292, R1236–R1245. [Google Scholar] [CrossRef]
  88. Hsu, C.N.; Hou, C.Y.; Chang-Chien, G.P.; Lin, S.; Chan, J.Y.H.; Lee, C.T.; Tain, Y.L. Maternal resveratrol therapy protected adult rat offspring against hypertension programmed by combined exposures to asymmetric dimethylarginine and trimethylamine-N-oxide. J. Nutr. Biochem. 2021, 93, 108630. [Google Scholar] [CrossRef]
  89. Tain, Y.L.; Lee, W.C.; Hsu, C.N.; Lee, W.C.; Huang, L.T.; Lee, C.T.; Lin, C.Y. Asymmetric dimethylarginine is associated with developmental programming of adult kidney disease and hypertension in offspring of streptozotocin-treated mothers. PLoS ONE 2013, 8, e55420. [Google Scholar] [CrossRef]
  90. Martínez Gascón, L.E.; Ortiz, M.C.; Galindo, M.; Sanchez, J.M.; Sancho-Rodriguez, N.; Albaladejo Otón, M.D.; Rodriguez Mulero, M.D.; Rodriguez, F. Role of heme oxygenase in the regulation of the renal hemodynamics in a model of sex dependent programmed hypertension by maternal diabetes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2022. [Google Scholar] [CrossRef]
  91. Yu, C.; Chen, S.; Wang, X.; Wu, G.; Zhang, Y.; Fu, C.; Hu, C.; Liu, Z.; Luo, X.; Wang, J.; et al. Exposure to maternal diabetes induces endothelial dysfunction and hypertension in adult male rat offspring. Microvasc. Res. 2021, 133, 104076. [Google Scholar] [CrossRef]
  92. Tain, Y.L.; Hsu, C.N.; Lee, C.T.; Lin, Y.J.; Tsai, C.C. N-Acetylcysteine prevents programmed hypertension in male rat offspring born to suramin-treated mothers. Biol. Reprod. 2016, 95, 8. [Google Scholar] [CrossRef] [PubMed]
  93. Tain, Y.L.; Lee, W.C.; Wu, K.L.H.; Leu, S.; Chan, J.Y.H. Targeting arachidonic acid pathway to prevent programmed hypertension in maternal fructose-fed male adult rat offspring. J. Nutr. Biochem. 2016, 38, 86–92. [Google Scholar] [CrossRef] [PubMed]
  94. Chao, Y.M.; Wu, K.L.H.; Tsai, P.C.; Tain, Y.L.; Leu, S.; Lee, W.C.; Chan, J.Y.H. Anomalous AMPK-regulated angiotensin AT1R expression and SIRT1-mediated mitochondrial biogenesis at RVLM in hypertension programming of offspring to maternal high fructose exposure. J. Biomed. Sci. 2020, 27, 68. [Google Scholar] [CrossRef] [PubMed]
  95. Tsai, P.C.; Chao, Y.M.; Chan, J.Y.H. Sympathetic activation of splenic T-lymphocytes in hypertension of adult offspring programmed by maternal high fructose exposure. Chin. J. Physiol. 2020, 63, 263–275. [Google Scholar]
  96. Tain, Y.L.; Lee, W.C.; Wu, K.L.H.; Leu, S.; Chan, J.Y.H. Resveratrol Prevents the Development of Hypertension Programmed by Maternal Plus Post-Weaning High-Fructose Consumption through Modulation of Oxidative Stress, Nutrient-Sensing Signals, and Gut Microbiota. Mol. Nutr. Food Res. 2018, 30, e1800066. [Google Scholar] [CrossRef]
  97. Tain, Y.L.; Chan, J.Y.H.; Lee, C.T.; Hsu, C.N. Maternal Melatonin Therapy Attenuates Methyl-Donor Diet-Induced Programmed Hypertension in Male Adult Rat Offspring. Nutrients 2018, 10, 1407. [Google Scholar] [CrossRef] [Green Version]
  98. Hsu, C.N.; Yang, H.W.; Hou, C.Y.; Chang-Chien, G.P.; Lin, S.; Tain, Y.L. Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites. Int. J. Mol. Sci. 2020, 21, 7237. [Google Scholar] [CrossRef]
  99. Hsu, C.N.; Hou, C.Y.; Chang-Chien, G.P.; Lin, S.; Yang, H.W.; Tain, Y.L. Perinatal Resveratrol Therapy Prevents Hypertension Programmed by Maternal Chronic Kidney Disease in Adult Male Offspring: Implications of the Gut Microbiome and Their Metabolites. Biomedicines 2020, 8, 567. [Google Scholar] [CrossRef]
  100. Do Nascimento, L.C.P.; Neto, J.P.R.C.; de Andrade Braga, V.; Lagranha, C.J.; de Brito Alves, J.L. Maternal exposure to high-fat and high-cholesterol diet induces arterial hypertension and oxidative stress along the gut-kidney axis in rat offspring. Life Sci. 2020, 261, 118367. [Google Scholar] [CrossRef]
  101. Lamothe, J.; Khurana, S.; Tharmalingam, S.; Williamson, C.; Byrne, C.J.; Lees, S.J.; Khaper, N.; Kumar, A.; Tai, T.C. Oxidative Stress Mediates the Fetal Programming of Hypertension by Glucocorticoids. Antioxidants 2021, 10, 531. [Google Scholar] [CrossRef]
  102. Tain, Y.L.; Sheen, J.M.; Chen, C.C.; Yu, H.R.; Tiao, M.M.; Kuo, H.C.; Huang, L.T. Maternal citrulline supplementation prevents prenatal dexamethasone-induced programmed hypertension. Free Radic. Res. 2014, 48, 580–586. [Google Scholar] [CrossRef] [PubMed]
  103. Tai, I.H.; Sheen, J.M.; Lin, Y.J.; Yu, H.R.; Tiao, M.M.; Chen, C.C.; Huang, L.T.; Tain, Y.L. Maternal N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and prevents programmed hypertension in male offspring exposed to prenatal dexamethasone and postnatal high-fat diet. Nitric Oxide 2016, 53, 6–12. [Google Scholar] [CrossRef] [PubMed]
  104. Hsu, C.N.; Lin, Y.J.; Yu, H.R.; Lin, I.C.; Sheen, J.M.; Huang, L.T.; Tain, Y.L. Protection of Male Rat Offspring against Hypertension Programmed by Prenatal Dexamethasone Administration and Postnatal High-Fat Diet with the Nrf2 Activator Dimethyl Fumarate during Pregnancy. Int. J. Mol. Sci. 2019, 20, 3957. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Hsu, C.N.; Lin, Y.J.; Lu, P.C.; Tain, Y.L. Maternal resveratrol therapy protects male rat offspring against programmed hypertension induced by TCDD and dexamethasone exposures: Is it relevant to aryl hydrocarbon receptor? Int. J. Mol. Sci. 2018, 19, 2459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Hsu, C.N.; Lin, Y.J.; Tain, Y.L. Maternal exposure to bisphenol A combined with high-fat diet-induced programmed hypertension in adult male rat offspring: Effects of resveratrol. Int. J. Mol. Sci. 2019, 20, 4382. [Google Scholar] [CrossRef] [Green Version]
  107. Ojeda, N.B.; Hennington, B.S.; Williamson, D.T.; Hill, M.L.; Betson, N.E.; Sartori-Valinotti, J.C.; Reckelhoff, J.F.; Royals, T.P.; Alexander, B.T. Oxidative stress contributes to sex differences in blood pressure in adult growth-restricted offspring. Hypertension 2012, 60, 114–122. [Google Scholar] [CrossRef] [Green Version]
  108. Tsai, W.L.; Hsu, C.N.; Tain, Y.L. Whether AICAR in Pregnancy or Lactation Prevents Hypertension Programmed by High Saturated Fat Diet: A Pilot Study. Nutrients 2020, 12, 448. [Google Scholar] [CrossRef] [Green Version]
  109. Feng, X.; Guo, Q.; Xue, H.; Duan, X.; Jin, S.; Wu, Y. Hydrogen Sulfide Attenuated Angiotensin II-Induced Sympathetic Excitation in Offspring of Renovascular Hypertensive Rats. Front. Pharmacol. 2020, 11, 565726. [Google Scholar] [CrossRef]
  110. Svitok, P.; Okuliarova, M.; Varga, I.; Zeman, M. Renal impairment induced by prenatal exposure to angiotensin II in male rat offspring. Exp. Biol. Med. (Maywood) 2019, 244, 923–931. [Google Scholar] [CrossRef]
  111. Piecha, G.; Koleganova, N.; Ritz, E.; Müller, A.; Fedorova, O.V.; Bagrov, A.Y.; Lutz, D.; Schirmacher, P.; Gross-Weissmann, M.L. High salt intake causes adverse fetal programming--vascular effects beyond blood pressure. Nephrol. Dial. Transplant. 2012, 27, 3464–3476. [Google Scholar]
  112. Liu, Y.; Qi, L.; Wu, J.; Xu, T.; Yang, C.; Chen, X.; Lv, J.; Xu, Z. Prenatal high-salt diet impaired vasodilatation with reprogrammed renin-angiotensin system in offspring rats. J. Hypertens. 2018, 36, 2369–2379. [Google Scholar] [CrossRef] [PubMed]
  113. Vieira, L.D.; Farias, J.S.; de Queiroz, D.B.; Cabral, E.V.; Lima-Filho, M.M.; Sant’Helena, B.R.M.; Aires, R.S.; Ribeiro, V.S.; Santos-Rocha, J.; Xavier, F.E.; et al. Oxidative stress induced by prenatal LPS leads to endothelial dysfunction and renal haemodynamic changes through angiotensin II/NADPH oxidase pathway: Prevention by early treatment with α-tocopherol. Biochim. Biophys. Acta Mol. Basis Dis. 2018, 1864, 3577–3587. [Google Scholar] [CrossRef] [PubMed]
  114. Zhu, Y.P.; Chen, L.; Wang, X.J.; Jiang, Q.H.; Bei, X.Y.; Sun, W.L.; Xia, S.J.; Jiang, J.T. Maternal exposure to di-n-butyl phthalate (DBP) induces renal fibrosis in adult rat offspring. Oncotarget 2017, 8, 31101–31111. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Hendricks, A.S.; Lawson, M.J.; Figueroa, J.P.; Chappell, M.C.; Diz, D.I.; Shaltout, H.A. Central ANG-(1-7) infusion improves blood pressure regulation in antenatal betamethasone-exposed sheep and reveals sex-dependent effects on oxidative stress. Am. J. Physiol. Heart Circ. Physiol. 2019, 316, H1458–H1467. [Google Scholar] [CrossRef] [PubMed]
  116. Gwathmey, T.M.; Shaltout, H.A.; Rose, J.C.; Diz, D.I.; Chappell, M.C. Glucocorticoid-induced fetal programming alters the functional complement of angiotensin receptor subtypes within the kidney. Hypertension 2011, 57, 620–626. [Google Scholar] [CrossRef] [Green Version]
  117. Chen, L.; Zadi, Z.H.; Zhang, J.; Scharf, S.M.; Pae, E.K. Intermittent hypoxia in utero damages postnatal growth and cardiovascular function in rats. J. Appl. Physiol. 2018, 124, 821–830. [Google Scholar] [CrossRef]
  118. Skeffington, K.L.; Beck, C.; Itani, N.; Niu, Y.; Shaw, C.J.; Giussani, D.A. Hypertension Programmed in Adult Hens by Isolated Effects of Developmental Hypoxia In Ovo. Hypertension 2020, 76, 533–544. [Google Scholar] [CrossRef]
  119. Brain, K.L.; Allison, B.J.; Niu, Y.; Cross, C.M.; Itani, N.; Kane, A.D.; Herrera, E.A.; Skeffington, K.L.; Botting, K.J.; Giussani, D.A. Intervention against hypertension in the next generation programmed by developmental hypoxia. PLoS Biol. 2019, 17, e2006552. [Google Scholar] [CrossRef] [Green Version]
  120. Hsu, C.N.; Tain, Y.L. The Good, the Bad, and the Ugly of Pregnancy Nutrients and Developmental Programming of Adult Disease. Nutrients 2019, 11, 894. [Google Scholar] [CrossRef] [Green Version]
  121. Sengupta, P. The laboratory rat: Relating its age with human’s. Int. J. Prev. Med. 2013, 4, 624–630. [Google Scholar]
  122. Bandookwala, M.; Sengupta, P. 3-Nitrotyrosine: A versatile oxidative stress biomarker for major neurodegenerative diseases. Int. J. Neurosci. 2020, 130, 1047–1062. [Google Scholar] [CrossRef] [PubMed]
  123. Tain, Y.L.; Hsu, C.N. Regulation of Nitric Oxide Production in the Developmental Programming of Hypertension and Kidney Disease. Int. J. Mol. Sci. 2019, 20, 681. [Google Scholar]
  124. Marrocco, I.; Altieri, F.; Peluso, I. Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans. Oxid. Med. Cell Longev. 2017, 2017, 6501046. [Google Scholar] [CrossRef] [PubMed]
  125. Kett, M.M.; Denton, K.M. Renal programming: Cause for concern? Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011, 300, R791–R803. [Google Scholar] [CrossRef]
  126. Tain, Y.L.; Hsu, C.N. Developmental Origins of Chronic Kidney Disease: Should We Focus on Early Life? Int. J. Mol. Sci. 2017, 18, 381. [Google Scholar] [CrossRef] [Green Version]
  127. Ortiz, L.A.; Quan, A.; Weinberg, A.; Baum, M. Effect of prenatal dexamethasone on rat renal development. Kidney Int. 2001, 59, 1663–1669. [Google Scholar] [CrossRef] [Green Version]
  128. Tain, Y.L.; Hsu, C.N.; Chan, J.Y.; Huang, L.T. Renal Transcriptome Analysis of Programmed Hypertension Induced by Maternal Nutritional Insults. Int. J. Mol. Sci. 2015, 16, 17826–17837. [Google Scholar] [CrossRef] [Green Version]
  129. Sheen, J.M.; Yu, H.R.; Tiao, M.M.; Chen, C.C.; Huang, L.T.; Chang, H.Y.; Tain, Y.L. Prenatal dexamethasone-induced programmed hypertension and renal programming. Life Sci. 2015, 132, 41–48. [Google Scholar] [CrossRef]
  130. Tain, Y.L.; Leu, S.; Wu, K.L.; Lee, W.C.; Chan, J.Y. Melatonin prevents maternal fructose intake-induced programmed hypertension in the offspring: Roles of nitric oxide and arachidonic acid metabolites. J. Pineal Res. 2014, 57, 80–89. [Google Scholar] [CrossRef]
  131. Thornburg, K.L. The programming of cardiovascular disease. J. Dev. Orig. Health Dis. 2015, 6, 366–376. [Google Scholar] [CrossRef]
  132. Tain, Y.-L.; Hsu, C.-N. Interplay between Oxidative Stress and Nutrient Sensing Signaling in the Developmental Origins of Cardiovascular Disease. Int. J. Mol. Sci. 2017, 18, 841. [Google Scholar] [CrossRef]
  133. Blackmore, H.L.; Ozanne, S.E. Programming of cardiovascular disease across the life-course. J. Mol. Cell. Cardiol. 2015, 83, 122–130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Itani, N.; Salinas, C.E.; Villena, M.; Skeffington, K.L.; Beck, C.; Villamor, E.; Blanco, C.E.; Giussani, D.A. The highs and lows of programmed cardiovascular disease by developmental hypoxia: Studies in the chicken embryo. J. Physiol. 2017, 596, 2991–3001. [Google Scholar] [CrossRef] [PubMed]
  135. Goto, K.; Ohtsubo, T.; Kitazono, T. Endothelium-Dependent Hyperpolarization (EDH) in Hypertension: The Role of Endothelial Ion Channels. Int. J. Mol. Sci. 2018, 19, 315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Stead, R.; Musa, M.G.; Bryant, C.L.; Lanham, S.A.; Johnston, D.A.; Reynolds, R.; Torrens, C.; Fraser, P.A.; Clough, G.F. Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation. J. Hypertens. 2016, 34, 452–463. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Tain, Y.L.; Hsu, C.N.; Lin, C.Y.; Huang, L.T.; Lau, Y.T. Aliskiren prevents hypertension and reduces asymmetric dimethylarginine in young spontaneously hypertensive rats. Eur. J. Pharmacol. 2011, 670, 561–565. [Google Scholar] [CrossRef]
  138. Stiemsma, L.T.; Michels, K.B. The role of the microbiome in the developmental origins of health and disease. Pediatrics 2018, 141, e20172437. [Google Scholar] [CrossRef] [Green Version]
  139. Hsu, C.N.; Hou, C.Y.; Hsu, W.H.; Tain, Y.L. Cardiovascular Diseases of Developmental Origins: Preventive Aspects of Gut Microbiota-Targeted Therapy. Nutrients 2021, 13, 2290. [Google Scholar] [CrossRef]
  140. Hsu, C.N.; Hou, C.Y.; Chang-Chien, G.P.; Lin, S.; Tain, Y.L. Maternal Garlic Oil Supplementation Prevents High-Fat Diet-Induced Hypertension in Adult Rat Offspring: Implications of H2S-Generating Pathway in the Gut and Kidneys. Mol. Nutr. Food Res. 2021, 65, e2001116. [Google Scholar] [CrossRef]
  141. Pisoschi, A.M.; Pop, A. The role of antioxidants in the chemistry of oxidative stress: A review. Eur. J. Med. Chem. 2015, 97, 55–74. [Google Scholar] [CrossRef]
  142. Nimse, S.B.; Palb, D. Free radicals, natural antioxidants, and their reaction mechanisms. RSC. Adv. 2015, 5, 27986–28006. [Google Scholar] [CrossRef] [Green Version]
  143. Azzi, A.; Ricciarelli, R.; Zingg, J.M. Non-antioxidant molecular functions of alpha-tocopherol (vitaminE). FEBS Lett. 2002, 519, 8–10. [Google Scholar] [CrossRef] [Green Version]
  144. Wang, J.; Yin, N.; Deng, Y.; Wei, Y.; Huang, Y.; Pu, X.; Li, L.; Zheng, Y.; Guo, J.; Yu, J.; et al. Ascorbic Acid Protects against Hypertension through Downregulation of ACE1 Gene Expression Mediated by Histone Deacetylation in Prenatal Inflammation Induced Offspring. Sci. Rep. 2016, 6, 39469. [Google Scholar] [CrossRef] [PubMed]
  145. Koeners, M.P.; Racasan, S.; Koomans, H.A.; Joles, J.A.; Braam, B. Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal l-arginine and antioxidants. Acta Physiol. 2007, 190, 329–338. [Google Scholar] [CrossRef] [PubMed]
  146. Racasan, S.; Braam, B.; van der Giezen, D.M.; Goldschmeding, R.; Boer, P.; Koomans, H.A.; Joles, J.A. Perinatal l-arginine and antioxidant supplements reduce adult blood pressure in spontaneously hypertensive rats. Hypertension 2004, 44, 83–88. [Google Scholar] [CrossRef] [Green Version]
  147. Schwedhelm, E.; Maas, R.; Freese, R.; Jung, D.; Lukacs, Z.; Jambrecina, A.; Spickler, W.; Schulze, F.; Boger, R.H. Pharmacokinetic and pharmacodynamics properties of oral l-citrulline and l-arginine: Impact on nitric oxide metabolism. Br. J. Clin. Pharmacol. 2008, 65, 51–59. [Google Scholar] [CrossRef]
  148. Hsu, C.N.; Tain, Y.L. Impact of Arginine Nutrition and Metabolism during Pregnancy on Offspring Outcomes. Nutrients 2019, 11, 1452. [Google Scholar] [CrossRef] [Green Version]
  149. Cynober, L.; Moinard, C.; De Bandt, J.P. The 2009 ESPEN Sir David Cuthbertson. Citrulline: A new major signaling molecule or just another player in the pharmaconutrition game? Clin. Nutr. 2010, 29, 545–551. [Google Scholar] [CrossRef]
  150. Fraga, C.G.; Croft, K.D.; Kennedy, D.O.; Tomás-Barberán, F.A. The effects of polyphenols and other bioactives on human health. Food Funct. 2019, 10, 514–528. [Google Scholar] [CrossRef] [Green Version]
  151. Urquiaga, I.; Leighton, F. Plant polyphenol antioxidants and oxidative stress. Biol. Res. 2000, 33, 55–64. [Google Scholar] [CrossRef]
  152. Rodrigo, R.; Gil, D.; Miranda-Merchak, A.; Kalantzidis, G. Antihypertensive role of polyphenols. Adv. Clin. Chem. 2012, 58, 22. [Google Scholar]
  153. Truong, V.L.; Jun, M.; Jeong, W.S. Role of resveratrol in regulation of cellular defense systems against oxidative stress. Biofactors 2018, 44, 36–49. [Google Scholar] [CrossRef] [PubMed]
  154. Xia, N.; Daiber, A.; Förstermann, U.; Li, H. Antioxidant effects of resveratrol in the cardiovascular system. Br. J. Pharmacol. 2017, 174, 1633–1646. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Care, A.S.; Sung, M.M.; Panahi, S.; Gragasin, F.S.; Dyck, J.R.; Davidge, S.T.; Bourque, S.L. Perinatal Resveratrol Supplementation to Spontaneously Hypertensive Rat Dams Mitigates the Development of Hypertension in Adult Offspring. Hypertension 2016, 67, 1038–1044. [Google Scholar] [CrossRef] [Green Version]
  156. Reiter, R.J.; Mayo, J.C.; Tan, D.X.; Sainz, R.M.; Alatorre-Jimenez, M.; Qin, L. Melatonin as an antioxidant: Under promises but over delivers. J. Pineal Res. 2016, 61, 253–278. [Google Scholar] [CrossRef]
  157. Hsu, C.N.; Huang, L.T.; Tain, Y.L. Perinatal Use of Melatonin for Offspring Health: Focus on Cardiovascular and Neurological Diseases. Int. J. Mol. Sci. 2019, 20, 5681. [Google Scholar] [CrossRef] [Green Version]
  158. Šalamon, Š.; Kramar, B.; Marolt, T.P.; Poljšak, B.; Milisav, I. Medical and Dietary Uses of N-Acetylcysteine. Antioxidants 2019, 8, 111. [Google Scholar] [CrossRef] [Green Version]
  159. Huang, S.H.; Leonard, S.; Shi, X.; Goins, M.R.; Vallyathan, V. Antioxidant activity of lazaroid (U-75412E) and its protective effects against crystalline silica-induced cytotoxicity. Free Radic. Biol. Med. 1998, 24, 529–536. [Google Scholar] [CrossRef]
  160. Vomund, S.; Schäfer, A.; Parnham, M.J.; Brüne, B.; Von Knethen, A. Nrf2, the Master Regulator of Anti-Oxidative Responses. Int. J. Mol. Sci. 2017, 18, 2772. [Google Scholar] [CrossRef] [Green Version]
  161. Wilcox, C.S. Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol. Ther. 2010, 126, 119–145. [Google Scholar] [CrossRef] [Green Version]
  162. Villanueva, C.; Kross, R.D. Antioxidant-induced stress. Int. J. Mol Sci. 2012, 13, 2091–2109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Tain, Y.L.; Hsu, C.N. AMP-Activated Protein Kinase as a Reprogramming Strategy for Hypertension and Kidney Disease of Developmental Origin. Int. J. Mol. Sci. 2018, 19, 1744. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Figure 1. Schema outlining how early-life environmental insults induce hypertension in later life via oxidative stress programming of various organ systems and regulatory hormones. Early-life insults cause an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO). ROS are derived from enzymes that produce superoxide radical (O2−) intracellularly, such as NADPH oxidase and xanthine oxidase. Excessive ROS can be offset by the action of antioxidant enzymes. The components of the antioxidant defense are superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (Cat), etc. Nitric oxide synthase (NOS) catalyzes l-arginine to produce NO. NO mediates vasodilation and opposes vasoconstrictor effects driven by ROS. Uncoupled NOS produces superoxide, which scavenges NO, leading to peroxynitrite (ONOO−) formation. Oxidative stress is a condition where ROS overwhelm the antioxidant system, leading to cellular injury in the form of damaged DNA, lipids, and proteins. During development, oxidative stress triggers the developmental programming of prime organs involved in the regulation of blood pressure (i.e., heart, kidneys, brain, and blood vessels) and regulatory hormones, leading to hypertension in later life.
Figure 1. Schema outlining how early-life environmental insults induce hypertension in later life via oxidative stress programming of various organ systems and regulatory hormones. Early-life insults cause an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO). ROS are derived from enzymes that produce superoxide radical (O2−) intracellularly, such as NADPH oxidase and xanthine oxidase. Excessive ROS can be offset by the action of antioxidant enzymes. The components of the antioxidant defense are superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (Cat), etc. Nitric oxide synthase (NOS) catalyzes l-arginine to produce NO. NO mediates vasodilation and opposes vasoconstrictor effects driven by ROS. Uncoupled NOS produces superoxide, which scavenges NO, leading to peroxynitrite (ONOO−) formation. Oxidative stress is a condition where ROS overwhelm the antioxidant system, leading to cellular injury in the form of damaged DNA, lipids, and proteins. During development, oxidative stress triggers the developmental programming of prime organs involved in the regulation of blood pressure (i.e., heart, kidneys, brain, and blood vessels) and regulatory hormones, leading to hypertension in later life.
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Figure 2. Oxidative stress and possible molecular pathways linked to the hypertension of developmental origins.
Figure 2. Oxidative stress and possible molecular pathways linked to the hypertension of developmental origins.
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Figure 3. Schema outlining the potential antioxidants as a reprogramming strategy to prevent the hypertension of developmental origins.
Figure 3. Schema outlining the potential antioxidants as a reprogramming strategy to prevent the hypertension of developmental origins.
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Table
Table 1. Summary of the oxidative-stress-related hypertension of developmental origins in animal models.
Table 1. Summary of the oxidative-stress-related hypertension of developmental origins in animal models.
Animal ModelsSpecies/
Gender		Age at Evaluation Mechanisms of Oxidative StressProgrammed Organ SystemRef.
Maternal caloric restriction dietSD rat/M12 weeks↑ Renal 8-OHdG expression, ↑ ADMA, ↓ NOKidneys[83,84]
Maternal caloric restriction dietWistar rat/M16 weeks↑ 3-NT, ↓ NOVessels[85]
Maternal caloric restriction dietSD rat/M6 months↑ Xanthine-oxidase expressionHeart[86]
Maternal protein restriction dietWistar rat/M12 weeks↑ F2-isoprostane, ↓ glutathioneKidneys[87]
Maternal L-NAME administrationSD rat/M12 weeks↑ Renal F2-isoprostaneKidneys[46]
Maternal ADMA administrationSD rat/M12 weeks↓ NOKidneys[88]
Streptozotocin-induced diabetesSD rat/M12 weeks↑ ADMA, ↓ NOKidneys[89]
Streptozotocin-induced diabetesSD rat/M12 weeks↑ Renal TBARS and 3-NTKidneys, vessels[90]
Streptozotocin-induced diabetesSD rat/M24 weeks↑ ROS, ↓ NO, ↓ SOD activityVessels[91]
Maternal suramin administrationSD rat/M12 weeks↑ ADMA, ↓ NOKidneys[92]
Maternal high-fructose dietSD rat/M12 weeks↑ Renal 8-OHdG expression, ↓ NOKidneys[93]
Maternal high-fructose dietSD rat/M12 weeks↑ NADPH-oxidase expression and MDABrain[94]
Maternal high-fructose dietSD rat/M24 weeks↑ ROSSpleen[95]
Maternal plus post-weaning high-fructose dietSD rat/M12 weeks↑ Renal 8-OHdG expressionKidneys[96]
Maternal methyl-deficient dietSD rat/M12 weeks↑ Renal 8-OHdG expressionKidneys[97]
Maternal high methyl-donor dietSD rat/M12 weeks↑ Renal 8-OHdG expressionKidneys[97]
Maternal adenine-induced CKDSD rat/M12 weeks↑ Renal 8-OHdG expression,↑ ADMA, ↓ NOKidneys[98,99]
Maternal high-fat and high-cholesterol dietSD rat/M & F90 days↓ SOD activity in M; ↑ Renal MDA level in FKidneys[100]
Prenatal dexamethasone exposureWistar rat/M & F14 weeks↑ NADPH-oxidase, ↓ Gpx1 expressionAdrenal glands[101]
Prenatal dexamethasone exposureSD rat/M16 weeks↓ Renal NOKidneys[102]
Prenatal dexamethasone exposure plus postnatal high-fat intakeSD rat/M16 weeks↑ Renal 8-OHdG expression, ↓ NOKidneys[103,104]
Prenatal dexamethasone plus TCDD exposureSD rat/M16 weeks↑ Renal 8-OHdG expression, ↑ ADMAKidneys[105]
Prenatal bisphenol A exposure plus high-fat dietSD rat/M16 weeks↑ Renal 8-OHdG expression, ↑ ADMA, ↓ NOKidneys[106]
Reduced uterine perfusionSD rat/M16 weeks↑ Urinary F2-isoprostane level & renal NADPH-oxidase-dependent superoxideKidneys[107]
Maternal plus post-weaning high-fat dietSD rat/M16 weeks↑ Renal 8-OHdG expressionKidneys[108]
Maternal 1K1C modelSD rat/M16 weeks↑ NADPH-oxidase expression, ↑ 3-NTBrain[109]
Maternal angiotensin II administrationWistar rat/M18 weeks↑ Renal ROSKidneys[110]
Maternal high-salt dietSD rat/M12 weeks↑ 3-NT, ↑ ADMAVessels[111]
Maternal high-salt dietWistar rat/M5 months↑ NADPH-oxidase expression, ↑ MDA level, ↓ Antioxidant activityVessels[112]
Prenatal LPSExposureWistar rat/M28 weeks↑ Renal MDAKidneys[113]
Maternal di-n-butyl phthalate exposureSD rat/M & F18 months↑ Renal ROSKidneys[114]
Prenatal betamethasone exposureSheep/M6 months↑ 4-HNEBrain[115]
Prenatal betamethasone exposureSheep/M & F18 months↑ ROS, ↓ NOKidneys[116]
Prenatal hypoxia exposureSD rat/M & F8 weeks↑ Lipid peroxidationHeart[117]
Prenatal hypoxia exposureChicken/M & F6 months↓ NOHeart, vessels[118]
Prenatal hypoxia exposureSheep/M & F9 months↓ NOVessels[119]
Studies tabulated according to animal models, species, and age at evaluation. ADMA—asymmetric dimethylarginine; 8-OHdG—8-hydroxy-2’-deoxyguanosine; TBARS—thiobarbituric acid reactive substances; 3-NT—3-nitrotyrosine; 4-NHE—4-hydroxynonenal; Gpx1—glutathione peroxidase 1; CKD—chronic kidney disease; LPS—lipopolysaccharide; SD—Sprague Dawley; M—male; F—female; L-NAME—NG-nitro-l-arginine methyl ester; MDA—malondialdehyde; TCDD—2,3,7,8-tetrachlorodibenzo-p-dioxin; 1K1C model—one kidney is removed and the other undergoes artery constriction.
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Tain, Y.-L.; Hsu, C.-N. Oxidative Stress-Induced Hypertension of Developmental Origins: Preventive Aspects of Antioxidant Therapy. Antioxidants 2022, 11, 511. https://doi.org/10.3390/antiox11030511

AMA Style

Tain Y-L, Hsu C-N. Oxidative Stress-Induced Hypertension of Developmental Origins: Preventive Aspects of Antioxidant Therapy. Antioxidants. 2022; 11(3):511. https://doi.org/10.3390/antiox11030511

Chicago/Turabian Style

Tain, You-Lin, and Chien-Ning Hsu. 2022. "Oxidative Stress-Induced Hypertension of Developmental Origins: Preventive Aspects of Antioxidant Therapy" Antioxidants 11, no. 3: 511. https://doi.org/10.3390/antiox11030511

APA Style

Tain, Y. -L., & Hsu, C. -N. (2022). Oxidative Stress-Induced Hypertension of Developmental Origins: Preventive Aspects of Antioxidant Therapy. Antioxidants, 11(3), 511. https://doi.org/10.3390/antiox11030511

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