Advances in Nanoscience and Nanotechnology

Statement of the Problem: Hemodynamic forces, i.e. pro-atherogenic oscillatory flow (OS) and atheroprotective pulsatile flow (PS), have been identified to be the vital factors to modulate endothelial cell (EC) dysfunction and function. However, the relationship between hormone receptor and microRNA (miRs) in hemodynamics-modulated EC function remain unclear. Methodology & Theoretical Orientation: The aim of this study is to elucidate the role of RARa-directed miR-10a signaling in hemodynamics-modulating EC function and dysfunction. In vitro flow system was used to generate OS and PS to investigate the effect of hemodynamic forces on miR-10a signaling and EC dysfunction, and its underlying mechanism. In vivo apolipoprotein E-deficient (ApoE-/-) mice model was used to evaluate the therapeutic effect of miR-10a on atherosclerosis. Conclusion & Significance: Our results showed that miR-10a is the miR with the lowest expression among all examined shear-responsive miRs in ECs in response to pro-atherogenic OS, and has relatively higher expression than other shear-responsive miRs in ECs in response to atheroprotective PS. MiR-10a targets transcriptional factor GATA6 to modulate pro-inflammatory VCAM-1, which is differentially regulated by atherogenic OS and atheroprotective PS. Mechanistically, hormone receptor RARα (director) and RXRα (enhancer) are induced by atheroprotective PS to form heterodimer in the nucleus to enhance miR-10a expression to inhibit pro-inflammatory GATA6/VCAM-1 signaling. In contrast, HDAC-3/-5/-7 (repressors) are induced by atherogenic OS to associate with RARα to repress RARα-directed miR-10a signaling. Finally, our data on ApoE-/- mice model demonstrated that systemic delivery of miR-10a induces the expression of endothelial miR-10a to repress GATA6/VCAM-1 signaling, and subsequently inhibits the formation of atherosclerosis. Our findings provide new insight that RXRα and HDAC-3/5/7 constitute a regulatory machinery to switch the role of hormone receptor RARα in modulating miR-10a/GATA6/VCAM-1 signaling in ECs in response to different flow patterns. Moreover, in vivo induction of endothelial miR-10a inhibits the 

progression of atherosclerosis.