MicroRNA-10a is crucial for endothelial response to different flows via interaction of retinoid acid receptors and histone deacetylases

Abstract

Histone deacetylases (HDACs) and microRNAs (miRs) have emerged as two important epigenetic factors in the regulation of vascular physiology. This study aimed to elucidate the relationship between HDACs and miRs in the hemodynamic modulation of endothelial cell (EC) dysfunction. We found that miR-10a has the lowest expression among all examined shear-responsive miRs in ECs under oscillatory shear stress (OS), and a relatively high expression under pulsatile shear stress (PS). PS and OS alter EC miR-10a expression to regulate the expression of its direct target GATA6 and downstream vascular cell adhesion molecule (VCAM)-1. PS induces the expression, nuclear accumulation, and association of retinoid acid receptor-alpha (RAR alpha) and retinoid X receptor-alpha (RXR alpha). RAR alpha and RXRa serve as a "director" and an "enhancer," respectively, to enhance RARa binding to RA-responsive element (RARE) and hence miR-10a expression, thus down-regulating GATA6/VCAM-1 signaling in ECs. In contrast, OS induces associations of " repressors" HDAC-3/5/7 with RARa to inhibit the RAR alpha-directed miR-10a signaling. The flow-mediated miR-10a expression is regulated by Kruppel-like factor 2 through modulation in RARa-RARE binding, with the consequent regulation in GATA6/VCAM-1 in ECs. These results are confirmed in vivo by en face staining on the aortic arch vs. the straight thoracic aorta of rats. Our findings identify a mechanism by which HDACs and RXRa modulate the hormone receptor RARa to switch miR-10a expression and hence the proinflammatory vs. anti-inflammatory responses of vascular endothelium under different hemodynamic forces.