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Molecular Research of Vascular Aspects in Pregnancy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 17214

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Special Issue Editor

Dr. Maurizio Mandalà

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Guest Editor

Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy
Interests: arteries; veins; hypertension; vascular remodeling; pregnancy; preeclampsia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although many aspects of pregnancy have been studied and described in detail, many others remain elusive. One such aspect concerns the molecular mechanisms involved in the gestational adaptation of the cardiovascular system. How these molecular pathways and signals can be altered in normal pregnancies vs. those complicated by gestational diseases such as preeclampsia/hypertension, intrauterine growth restriction (IUGR), and diabetes is not well understood.

The aim of this Special Issue is to provide a perspective on our current understanding of cardiovascular adaptation in physiological and complicated pregnancies, with a focus on the molecular level, and to highlight the most promising and novel areas of research.

Dr. Maurizio Mandalà
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

vascular system
endothelial cells
smooth muscle cells
pregnancy
preeclampsia
cardiovascular diseases
intrauterine growth restriction (IUGR)
heart disease
hypertension

Published Papers (7 papers)

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Research

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12 pages, 1481 KiB

Open AccessCommunication

ICI 182,780 Attenuates Selective Upregulation of Uterine Artery Cystathionine β-Synthase Expression in Rat Pregnancy

by Jin Bai, Yao Li, Guofeng Yan, Jing Zhou, Alejandra Garcia Salmeron, Olamide Tolulope Fategbe, Sathish Kumar, Xuejin Chen and Dong-Bao Chen

Int. J. Mol. Sci. 2023, 24(18), 14384; https://doi.org/10.3390/ijms241814384 - 21 Sep 2023

Viewed by 1191

Abstract

Endogenous hydrogen sulfide (H₂S) produced by cystathionine β-synthase (CBS) and cystathionine-γ lyase (CSE) has emerged as a novel uterine vasodilator contributing to pregnancy-associated increases in uterine blood flow, which safeguard pregnancy health. Uterine artery (UA) H₂S production is stimulated via exogenous estrogen replacement and is associated with elevated endogenous estrogens during pregnancy through the selective upregulation of CBS without altering CSE. However, how endogenous estrogens regulate uterine artery CBS expression in pregnancy is unknown. This study was conducted to test a hypothesis that endogenous estrogens selectively stimulate UA CBS expression via specific estrogen receptors (ER). Treatment with E₂β (0.01 to 100 nM) stimulated CBS but not CSE mRNA in organ cultures of fresh UA rings from both NP and P (gestational day 20, GD20) rats, with greater responses to all doses of E₂β tested in P vs. NP UA. ER antagonist ICI 182,780 (ICI, 1 µM) completely attenuated E₂β-stimulated CBS mRNA in both NP and P rat UA. Subcutaneous injection with ICI 182,780 (0.3 mg/rat) of GD19 P rats for 24 h significantly inhibited UA CBS but not mRNA expression, consistent with reduced endothelial and smooth muscle cell CBS (but not CSE) protein. ICI did not alter mesenteric and renal artery CBS and CSE mRNA. In addition, ICI decreased endothelial nitric oxide synthase mRNA in UA but not in mesenteric or renal arteries. Thus, pregnancy-augmented UA CBS/H₂S production is mediated by the actions of endogenous estrogens via specific ER in pregnant rats. Full article

(This article belongs to the Special Issue Molecular Research of Vascular Aspects in Pregnancy)

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12 pages, 2991 KiB

Open AccessArticle

Serum Collected from Preeclamptic Pregnancies Drives Vasoconstriction of Human Omental Arteries—A Novel Ex Vivo Model of Preeclampsia for Therapeutic Development

by Bianca R. Fato, Natasha de Alwis, Sally Beard, Natalie K. Binder, Natasha Pritchard, Stephen Tong, Tu’uhevaha J. Kaitu’u-Lino and Natalie J. Hannan

Int. J. Mol. Sci. 2022, 23(18), 10852; https://doi.org/10.3390/ijms231810852 - 16 Sep 2022

Cited by 1 | Viewed by 1689

Abstract

New-onset maternal hypertension is a hallmark of preeclampsia, driven by widespread endothelial dysfunction and systemic vasoconstriction. Here, we set out to create a new ex vivo model using preeclamptic serum to cause injury to the endothelium, mimicking vascular dysfunction in preeclampsia and offering the potential to evaluate candidate therapeutic interventions. Human omental arteries were collected at caesarean section from normotensive pregnant patients at term (n = 9). Serum was collected from pregnancies complicated by preterm preeclampsia (birth < 34 weeks’ gestation, n = 16), term preeclampsia (birth > 37 weeks’ gestation, n = 5), and healthy gestation-matched controls (preterm n = 16, term n = 12). Using wire myography, we performed ex vivo whole vessel assessment where human omental arteries were treated with increasing doses of each serum treatment (2–20%) and vasoreactivity was assessed. All pregnant serum treatments successfully drove vasoconstriction; no significant difference was observed in the degree of vasoconstriction when exposed to preeclamptic or control serum. We further demonstrated the ability of esomeprazole (a candidate therapeutic for preeclampsia; 0.1–100 µM) to drive vasorelaxation of pre-constricted vessels (only with serum from preeclamptic patients). In summary, we describe a novel human physiological model of preeclamptic vascular constriction. We demonstrate its exciting potential to screen drugs for their therapeutic potential as treatment for vasoconstriction induced by preeclampsia. Full article

(This article belongs to the Special Issue Molecular Research of Vascular Aspects in Pregnancy)

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15 pages, 3137 KiB

Open AccessArticle

Advanced Maternal Age Impairs Uterine Artery Adaptations to Pregnancy in Rats

by Amy L. Wooldridge, Mazhar Pasha, Palehswan Chitrakar, Raven Kirschenman, Anita Quon, Floor Spaans, Tamara Sáez, Christy-Lynn M. Cooke and Sandra T. Davidge

Int. J. Mol. Sci. 2022, 23(16), 9191; https://doi.org/10.3390/ijms23169191 - 16 Aug 2022

Cited by 8 | Viewed by 2363

Abstract

Advanced maternal age (≥35 years) is associated with pregnancy complications. Aging impairs vascular reactivity and increases vascular stiffness. We hypothesized that uterine artery adaptations to pregnancy are impaired with advanced age. Uterine arteries of nonpregnant and pregnant (gestational day 20) young (4 months) and aged (9 months; ~35 years in humans) Sprague-Dawley rats were isolated. Functional (myogenic tone, n = 6–10/group) and mechanical (circumferential stress-strain, n = 10–24/group) properties were assessed using pressure myography and further assessment of elastin and collagen (histology, n = 4–6/group), and matrix metalloproteinase-2 (MMP-2, zymography, n = 6/group). Aged dams had worse pregnancy outcomes, including smaller litters and fetal weights (both p < 0.0001). Only in arteries of pregnant young dams did higher pressures (>100 mmHg) cause forced vasodilation. Across the whole pressure range (4–160 mmHg), myogenic behavior was enhanced in aged vs. young pregnant dams (p = 0.0010). Circumferential stress and strain increased with pregnancy in young and aged dams (p < 0.0001), but strain remained lower in aged vs. young dams (p < 0.05). Arteries from young nonpregnant rats had greater collagen:elastin ratios than the other groups (p < 0.05). In aged rats only, pregnancy increased MMP-2 active capacity. Altered functional and structural vascular adaptations to pregnancy may impair fetal growth and development with advanced maternal age. Full article

(This article belongs to the Special Issue Molecular Research of Vascular Aspects in Pregnancy)

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11 pages, 886 KiB

Open AccessArticle

G-Protein-Coupled Estrogen Receptor Expression in Rat Uterine Artery Is Increased by Pregnancy and Induces Dilation in a Ca²⁺ and ERK1/2 Dependent Manner

by Teresa Tropea, Damiano Rigiracciolo, Milena Esposito, Marcello Maggiolini and Maurizio Mandalà

Int. J. Mol. Sci. 2022, 23(11), 5996; https://doi.org/10.3390/ijms23115996 - 26 May 2022

Cited by 6 | Viewed by 1889

Abstract

Increasing levels of estrogens across gestation are partly responsible for the physiological adaptations of the maternal vasculature to pregnancy. The G protein-coupled estrogen receptor (GPER) mediates acute vasorelaxing effects in the uterine vasculature, which may contribute to the regulation of uteroplacental blood flow. The aim of this study was to investigate whether GPER expression and vasorelaxation may occur following pregnancy. Elucidation of the functional signalling involved was also investigated. Radial uterine and third-order mesenteric arteries were isolated from non-pregnant (NP) and pregnant rats (P). GPER mRNA levels were determined and—concentration–response curve to the GPER-specific agonist, G1 (10⁻¹⁰–10⁻⁶ M), was assessed in arteries pre-constricted with phenylephrine. In uterine arteries, GPER mRNA expression was significantly increased and vasorelaxation to G1 was significantly enhanced in P compared with NP rats. Meanwhile, in mesenteric arteries, there was a similar order of magnitude in NP and P rats. Inhibition of L-type calcium channels and extracellular signal-regulated kinases 1/2 significantly reduced vasorelaxation triggered by G1 in uterine arteries. Increased GPER expression and GPER-mediated vasorelaxation are associated with the advancement of gestation in uterine arteries. The modulation of GPER is exclusive to uterine arteries, thus suggesting a physiological contribution of GPER toward the regulation of uteroplacental blood flow during pregnancy. Full article

(This article belongs to the Special Issue Molecular Research of Vascular Aspects in Pregnancy)

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Review

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21 pages, 2296 KiB

Open AccessReview

Literature Review: The sFlt1/PlGF Ratio and Pregestational Maternal Comorbidities: New Risk Factors to Predict Pre-Eclampsia

by Nataliia Sergeevna Karpova, Olga Pavlovna Dmitrenko and Tatyana Sergeevna Budykina

Int. J. Mol. Sci. 2023, 24(7), 6744; https://doi.org/10.3390/ijms24076744 - 4 Apr 2023

Cited by 1 | Viewed by 4902

Abstract

One of the main causes of maternal and neonatal morbidity and mortality is pre-eclampsia. It is characterized by a high sFlt1/PlGF ratio, according to prior research. Pregestational diseases in mothers may increase the risk of developing pre-eclampsia. Only a few studies have looked at the connection between maternal comorbidities before conception and the sFlt1/PlGF ratio. The most recent information regarding the association between maternal pregestational diseases and the ratio of sFlt1/PlGF is described in this review. The paper also examines current research suggesting that changes in pregnancy hormones and metabolites are related to a high sFlt1/PlGF ratio. Certain maternal disorders have been found to dramatically raise sFlt-1 and sFlt1/PlGF levels, according to an analysis of the literature. There is still debate about the data on the association between the sFlt1/PlGF ratio and maternal disorders such as HIV, acute coronary syndromes, cardiovascular function in the mother between 19 and 23 weeks of pregnancy, thyroid hormones, diabetes, and cancer. Additional research is needed to confirm these findings. Full article

(This article belongs to the Special Issue Molecular Research of Vascular Aspects in Pregnancy)

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16 pages, 1611 KiB

Open AccessReview

Vascular Endothelial Growth Factor Receptor 2: Molecular Mechanism and Therapeutic Potential in Preeclampsia Comorbidity with Human Immunodeficiency Virus and Severe Acute Respiratory Syndrome Coronavirus 2 Infections

by Tashlen Abel, Jagidesa Moodley, Olive P. Khaliq and Thajasvarie Naicker

Int. J. Mol. Sci. 2022, 23(22), 13752; https://doi.org/10.3390/ijms232213752 - 9 Nov 2022

Cited by 3 | Viewed by 2256

Abstract

This review explored the role of vascular endothelial growth factor receptor-2 (VEGFR-2) in the synergy of preeclampsia (PE), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Downregulation of VEGFR-2 in PE promotes endothelial dysfunction and prevents endothelial cell (EC) migration, proliferation, and differentiation. The HIV-1 accessory protein, tat (trans-activator of transcription), prevents VEGFR-2 signaling via the vascular endothelial growth factor A (VEGF-A) ligand. Combined antiretroviral therapy (cART) may cause immune reconstitution, impaired decidualization, and endothelial injury, thus may be a risk factor for PE development. The VEGF/VEGFR-2 interaction may be associated with SARS-CoV-2-related pulmonary oedema. Endothelial dysfunction and heightened inflammation are both associated with PE, HIV, and SARS-CoV-2 infection; therefore, it is plausible that both characteristics may be exacerbated in the synergy of these events. In addition, this review explored microRNAs (miR) regulating VEGFR-2. An overexpression of miR-126 is evident in PE, HIV, and SARS-CoV-2 infection; thus, modulating the expression of miR-126 may be a therapeutic strategy. However, the involvement of microRNAs in PE, HIV, and SARS-CoV-2 infection needs further investigating. Since these conditions have been evaluated independently, this review attempts to predict their clinical manifestations in their synergy, as well as independently; thereby providing a platform for early diagnosis and therapeutic potential in PE, HIV, and SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Molecular Research of Vascular Aspects in Pregnancy)

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17 pages, 907 KiB

Open AccessReview

Potassium Channels in the Uterine Vasculature: Role in Healthy and Complicated Pregnancies

by Wyanet Bresnitz and Ramón A. Lorca

Int. J. Mol. Sci. 2022, 23(16), 9446; https://doi.org/10.3390/ijms23169446 - 21 Aug 2022

Cited by 3 | Viewed by 2094

Abstract

A progressive increase in maternal uterine and placental blood flow must occur during pregnancy to sustain the development of the fetus. Changes in maternal vasculature enable an increased uterine blood flow, placental nutrient and oxygen exchange, and subsequent fetal development. K⁺ channels are important modulators of vascular function, promoting vasodilation, inducing cell proliferation, and regulating cell signaling. Different types of K⁺ channels, such as Ca²⁺-activated, ATP-sensitive, and voltage-gated, have been implicated in the adaptation of maternal vasculature during pregnancy. Conversely, K⁺ channel dysfunction has been associated with vascular-related complications of pregnancy, including intrauterine growth restriction and pre-eclampsia. In this article, we provide an updated and comprehensive literature review that highlights the relevance of K⁺ channels as regulators of uterine vascular reactivity and their potential as therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Research of Vascular Aspects in Pregnancy)

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