Endothelial Epigenetics in Biomechanical Stress

Abstract

Arterial endothelial phenotype is regulated by local hemodynamic forces that are linked to regional susceptibility to atherogenesis. A complex hierarchy of transcriptional, translational and posttranslational mechanisms are greatly influenced by the characteristics of local arterial shear stress environments. We discuss the emerging role of localized disturbed blood flow upon epigenetic mechanisms of endothelial responses to biomechanical stress, including transcriptional regulation by proximal promoter DNA methylation, and posttranscriptional and translational regulation of gene and protein expression by chromatin remodeling and noncoding RNA-based mechanisms. Dynamic responses to flow characteristics in vivo and in vitro include site-specific differentially methylated regions of swine and mouse endothelial methylomes, histone marks regulating chromatin conformation, microRNAs and long noncoding RNAs. 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 promote atherosusceptibility.

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

“…Whatever the mechanism is, one could envision the regulation of α5 activation by both mechanical and biochemical actions to play a key role in EC dysfunction and atherosclerosis. This thesis is in line with that proposed by Davies and colleagues that the synergism between flow characteristics and hypercholesterolemia deserves "further evaluation of the epigenetic and epigenomic regulation of endothelial phenotype adaptation during early pathological change" (31,34).…”

Endothelial fluid shear stress sensing in vascular health and disease

“…13). Recently, epigenetic marks have also been observed (18,19). Of particular relevance for understanding disease, most studies have primarily focused on differential effects of onset of physiological levels of steady laminar flow as a model for stable vessels versus oscillatory shear stress as a model for Endothelial cells transduce the frictional force from blood flow (fluid shear stress) into biochemical signals that regulate gene expression and cell behavior via specialized mechanisms and pathways.…”

Endothelium

“…Epigenetic modifications taking place in endothelial cells have been elegantly reviewed in a recent mini-series. [5][6][7] Current epigenetic studies focus on protein coding-genes, and it remains unknown if such modifications also regulate nonprotein-coding genes and whether or not long noncoding RNAs play a role. Better understanding of endothelial epigenetic modifications, in particular under different flow conditions, will certainly improve the identification of new therapeutic targets in cardiovascular disease.…”