Mechanical regulation of epigenetics in vascular biology and pathobiology

Abstract

Vascular endothelial cells (ECs) and smooth muscle cells (VSMCs) are constantly exposed to haemodynamic forces, including blood flow-induced fluid shear stress and cyclic stretch from blood pressure. These forces modulate vascular cell gene expression and function and, therefore, influence vascular physiology and pathophysiology in health and disease. Epigenetics, including DNA methylation, histone modification/chromatin remodelling and RNA-based machinery, refers to the study of heritable changes in gene expression that occur without changes in the DNA sequence. The role of haemodynamic force-induced epigenetic modifications in the regulation of vascular gene expression and function has recently been elucidated. This review provides an introduction to the epigenetic concepts that relate to vascular physiology and pathophysiology. Through the studies of gene expression, cell proliferation, angiogenesis, migration and pathophysiological states, we present a conceptual framework for understanding how mechanical force-induced epigenetic modifications work to control vascular gene expression and function and, hence, the development of vascular disorders. This research contributes to our knowledge of how the mechanical environment impacts the chromatin state of ECs and VSMCs and the consequent cellular behaviours.

Fig. 1

Schematic diagram showing the generations of shear stress (parallel to the endothelial surface), normal stress (i.e. pressure; perpendicular to the endothelial surface), and circumferential stretch because of blood flow and pressure (from Chiu and Chien 2).

Fig. 2

Schematic diagram of HDAC signalling and its modulation of gene expression and function in ECs in response to oscillatory and pulsatile flow. Oscillatory flow induces the expression and nuclear accumulation of class I HDAC1/2/3 and class II HDAC5/7 in ECs. Oscillatory flow induces associations of HDAC1/2/3 with Nrf-2, causing the deacetylation of Nrf-2 and inhibition of binding of Nrf-2 to the antioxidant response element (ARE), which result in the repression of NQO1 expression. Furthermore, HDAC1/2/3 are involved in the oscillatory flow-induced cell cycle progression and proliferation of ECs. In addition, oscillatory flow induces associations of HDAC3/5/7 with MEF-2, which lead to the inhibition of KLF-2 expression as a result of MEF-2 deacetylation. In contrast, pulsatile flow induces the phosphorylation-dependent nuclear export of HDAC5/7 in ECs, and hence induces the expressions of NQO-1 and KLF-2 (from Lee et al. 65).

Fig. 3

Schematic diagram of miRNAs and their function in ECs in response to shear stress. Oscillatory flow induces the expression of miR-92a, miR-21 and miR-663, leading to the repression of KLF-2 and PPAR-α expressions and an inflammatory response in ECs. Laminar shear stress induces the expressions of miR-19a and miR-23b, resulting in cell cycle arrest in ECs.