**6. Micro-RNA and its epigenetic role in endothelial pathophysiology**

Indisputably, microRNAs are fundamental regulators of many biological processes. Regulation of basic vascular endothelial functions by microRNAs and its disruption can lead to endothelial dysfunction. MicroRNAs are small, generally noncoding RNAs that regulate the expression of many genes through post-transcriptional degradation or translational repression. The crucial importance of microRNAs in endothelial physiology has been demonstrated following EC-specific inactivation of the enzyme Dicer which is involved in the biogenesis and processing of microRNAs, which cleaves microRNA precursors into mature forms [72, 73]. The absence of Dicer in the endothelium leads to altered expression of key regulators of endothelial function, including endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor receptor 2 (VEGF), interleukin-8, Tie-1 and Tie-2.

Recent studies have identified miR-19a as an important driver of upregulation of important factors implicated in endothelial dysfunction, hyperlipidemia, inflammation and atherosclerosis, revealing a vicious cycle involving endothelial Hif-1a activation, hyperlipidemia and upregulation of miR-19a, promoting CXCR2 (C-X-C Motif Chemokine Receptor 2 which mediates neutrophil migration to sites of inflammation) dependent monocyte adhesion by increasing endothelial expression of its ligand CXCL1 [74]. It is also worth noting that microRNAs are also involved in switching the phenotype of VSMCs between a quiescent (pro-contractile, differentiated) and proliferative (pro-synthetic, differentiated) state [75], a critical step in the pathophysiology of atherosclerosis.

The endothelium has a critical role in maintaining vascular integrity and protecting against cardiovascular disease. Accumulated data indicate endothelial function is a heritable trait regulated by polygenic factors; however, these genetic factors have not been fully elucidated until now.
