*3.3. Epigenomic Regulation in Endothelial Cell Dysregulation*

While VSMCs comprise a major part of the medial layer of vascular wall, the endothelial cells which line the walls are in direct contact with circulating stimuli and their contribution to the BP control has been extensively studied. It has been widely accepted that endothelial dysfunction plays an important role in systemic hypertension. Both DNA methylation and histone modification have been implicated in the regulation of endothelial cells in hypertension.

The endothelium releases various vasoactive factors, some of which are vasodilatory, e.g., nitric oxide (NO), prostacyclin (PGI2), and endothelium derived hyperpolarizing factor (EDHF); while some of which are vasoconstrictive, e.g., thromboxane (TXA2) and endothelin-1 (ET-1) [82]. The endothelial nitric oxide synthase (eNOS), which is expressed primarily in endothelial cells, is the primary mechanism by which NO is produced in the vessel. Disturbances in the NO pathway have been linked to the predominance of vasoconstrictors which feed vicious cycles to maintain high BP [83]. Notably, the expression of eNOS may be controlled by cell-specific histone modifications as acetylated histone H3 lysine 9, histone H4 lysine 12, and di- and tri-methylated lysine 4 of histone H3 are all present in the *NOS3* gene promoter in human umbilical vein endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC) but are absent in non-eNOS expressing cells like VSMCs and HeLa cells [22]. This mechanism was further explained by the discovery of HDAC1 selectively bound to the *NOS3* gene promoter in VSMCs, thus reducing the histone acetylation and transcription of eNOS in SMC [22]. Epigenetic regulation of eNOS expression is key to the tissue specificity observed in NO and dysregulation of epigenetic signaling during disease may contribute to increased vascular tone as a result of decreased NO synthesis in vessels.

In addition, an experiment in the deoxycorticosterone acetate (DOCA) salt-sensitive hypertension model of the Wistar rat, showed that animals treated with resveratrol, a known antihypertensive agent, increased the total antioxidant capacity and hydrogen sulfide levels which are independent of the change NO levels in circulation [84]. It also showed that resveratrol altered the staining of the H3K27me3 pattern of the aorta and renal artery sections, suggesting that its protective effects may be due to its effects of epigenetic modifications of the vessels [84].
