The Epigenomic Code in Hemodynamic Regulation of Cell Phenotypes in Atherosusceptible Endothelium

Abstract

Hemodynamics creates a constantly changing physical and chemical environment to which the arterial endothelium is exquisitely sensitive. Near branching anatomical sites in large and distributing arteries, blood flow separates from the main flow undergoing complex multi‐directional characteristics for a part of each cardiac cycle (collectively referred to as disturbed flow). Atherosclerosis develops preferentially at disturbed flow locations if an additional cardiovascular risk factor such as hypercholesterolemia is present. In the pre‐disease state, an atherosusceptible endothelial phenotype is characteristically present in such regions in contrast to the adjacent endothelium.A regulatory hierarchy of mechanisms control endothelial gene and protein expression (and function) in response to the flow environment. Gene expression regulation, the transcription of the DNA (genomic) code to mRNA, is well described by transcription factors, enhancers and repressors, many of which are flow responsive. However, emerging studies describe the additional role of localized disturbed blood flow upon epigenomic mechanisms of endothelial responses to biomechanical stress. Epigenetics and epigenomics encompass heritable and non‐heritable changes in nuclear chromatin leading to gene expression changes that cannot be attributed to changes in the primary DNA sequence. Hemodynamic stimuli have recently been shown to induce epigenomic responses including transcriptional regulation by proximal promoter DNA methylation, and regulation of gene and protein expression by histone/chromatin remodeling and by noncoding RNA‐based mechanisms.Dynamic epigenomic responses to flow that result in regulation of endothelial gene expression in vivo and in vitro include: (i) regions of stable differentially methylated DNA in swine and mouse endothelial genomes that arearterial site‐specific and map to atherosusceptibility, (ii) disturbed flow(but not undisturbed flow) applied to endothelial cells in vitro that induces DNA methylation through DNA methyltransferase enrichment of gene promoter regions; the resulting methylation suppresses gene expression, (iii) histone acetylation/deacetylation and methylation that create histone marks that enable or suppress gene expression by controlling access of transcription factors to chromatin DNA, and (iv) short microRNAs and long noncoding RNAs that interact with highly specific binding sites of promoter DNA. Flow‐mediated epigenomic responses intersect with cis and trans factor regulation to maintain endothelial function in a shear‐stressed environment and may contribute to localized endothelial dysfunctions that promoteatherosusceptibility.The epigenomic code therefore has the potential to figure prominently in disease susceptibility and pathogenesis arising from environmental influences independent of, or in concert with, mutations and single nucleotide polymorphisms (SNP) linked to many complex diseases, including cardiovascular disease. The role of disturbed flow as a hemodynamic regulator of epigenomic DNA methylation‐mediated and histone‐mediated gene expression may play a prominent role in endothelial vascular function and dysfunction. The mechanisms that link hemodynamics to the epigenomic code have not been identified.Support or Funding InformationSupported by AHA Postdoctoral Fellowship 13POST14070010, NIH (NHLBI) grants T32 HL07954 and P01 HL06220.