**1. Introduction**

Systemic hypertension (or Hypertension in this review) refers to a condition of high blood pressure (BP) in the systemic arteries, the vessels that carry blood from the heart to the body's tissues, which distinguishes the condition from a local high BP such as in pulmonary (lung) hypertension. Hypertension has been defined as a BP reading of 140/90 mm Hg or higher in adults for many years. However, the latest report (2017) from the American College of Cardiology/American Heart Association (ACC/AHA) provides an updated guideline that classifies hypertension as a BP reading of 130/80 mm Hg or higher [1]. Hypertension remains a major risk factor for myocardial infarction, heart failure, end-stage renal disease, and stroke despite extensive research for decades and many therapeutic approaches [2]. Hypertension affects nearly one third of all adults in the US and only one half of the hypertensive patients have their BP under control [3]. The ACC/AHA report also notes that males are more likely to develop hypertension compared to women at the pre-menopausal ages, suggesting a role for hormone signaling in the management of BP [1]. Although the causes of hypertension have not been fully outlined, certain chronic conditions may increase the risk of the development of hypertension which include general risk factors such as aging, smoking, low socioeconomic and educational status, overweight/obesity, unhealthy diet, and physical inactivity as well as other secondary disorders such as chronic kidney disease (CKD), genetic family history, diabetes mellitus, obstructive sleep apnea and psychosocial stress [1]. Current nonpharmacological therapy focuses on maintaining

a healthy diet, exercise, and other lifestyle changes, while pharmacological treatment includes: thiazide or thiazide-type diuretics, angiotensin-converting enzyme (ACE) inhibitors, dihydropyridines, aldosterone receptor blockers (spironolactone and derivatives), beta blockers, and vasodilators, direct renin inhibitors, and alpha-1 blockers [1]. Despite the plethora of treatment options, the high BP of 16.1 million hypertensive patients remains uncontrolled [3].

While many signaling pathways involved in the development of hypertension have been discovered, the molecular mechanisms related to the epigenomic regulation underlying vascular dysfunction are still not well understood. Epigenomics refers to the genome-wide study of gene regulation that alters gene activity without changing the DNA sequence [2]. Epigenomic regulation provides a link between the genotype and phenotype and is essential for many normal cellular functions, and inappropriate regulation at the epigenomic level may lead to some major adverse effects on cellular function of a tissue or organ which may lead to the development of diseases. Different epigenetic regulations have been identified in hypertension, including methylation, acetylation, phosphorylation, ubiquitination, and sumolyation.

It has been well-known that the renin-angiotensin-aldosterone system (RAAS), a hormone system that is integral to the physiological regulation of BP, plays a crucial role in the development of hypertension, thus, the epigenomic alterations of RAAS-regulated genes and their effects have been extensively tested in hypertensive models [4]. Increasing evidence is emerging that epigenomics also plays an important role in gene expression which may alter the phenotype and function of the vascular wall or cells in response to environmental stresses [5], underscoring our need to consider the contribution of epigenomic regulation of the vascular walls to hypertension. This review seeks to highlight recent advances in our knowledge of the changes in DNA methylation and histone modification which occur during the development of hypertension, as summarized in Table 1. Despite the well-known importance of RAAS in the development of hypertension, we have only briefly summarized them in this present manuscript since the relative epigenomic alterations of RAAS have been extensively discussed in a recent review [4]. To concentrate on the updated information, our present review focuses on the contribution of alterations to the vasculature in the development of systemic hypertension. An increased understanding of the epigenomic regulation of these vascular cells will lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of hypertension.


**Table 1.** DNA methylation and histone modification associated with hypertension.


#### **Table 1.** *Cont.*

Abbreviations: 5mc—5-methylcytosine, RAAS—Renin-angiotensin-aldosterone system, PBMC—peripheral blood mononuclear cell, SHR—spontaneously hypertensive rats, VSMC—vascular smooth muscle cell, HUVEC—human umbilical vein endothelial cell, HMVEC—human dermal microvascular endothelial cells, H3Ac—Histone 3 acetylation, H3K4me2—dimethylation of histone 3 lysine 4, H3K4me3—trimethylation of histone 3 lysine 4.
