Abstract 325: Atheroprone Flow Enhances the Endothelial-to-Mesenchymal Transition

Abstract

Introduciton and Hypothesis: The endothelial-to-mesenchymal transition (EndoMT) is a pathophysiological process in the vascualture, manifested by the decreased expression of endothelial markers (vWF, CD31, and VE-cadherin) but increased mesenchymal genes (e.g., N-cadherin, FSP1, and vimentin). In light of the involvement of EndoMT in the pathogenesis of atherosclerosis, we hypothesize that atheroprotective pulasatile shear stress (PS) and atheroprone oscillatory shear stress (OS) have opposite effect in regulating the EndoMT genes in vascular endothelial cells (ECs). Methods and Results: RNA sequencing data from multi-timepoint shear stress experiments show that PS and OS had an opposite effect in regulating EndoMT genes in ECs. Further experimental validations with H 2 O 2 and gain- and loss-of-function approaches indicated that reactive oxygen species were involved in the OS-induced EndoMT, whereas AMP-activated protein kinase and sirtuin-1 could inhibit the OS-induced EndoMT. Compared with PS, OS increased the DNA methylation of the promoter region of vWF , CD31 , and CDH5 genes but decreased that of CDH2 , FSP1 , and vimentin genes. In vivo , EndoMT was evident in the partially ligated mouse carotid artery where flow pattern is disturbed. Furthermore, the anti-diabetic drug metformin and cholesterol-lowering drug atorvastatin suppressed EndoMT in ECs and in mouse aortae. Conclusions: Genome-wide analysis of mRNA expression profiles and conventional experimental validations revealed that atheroprotective and atheroprone flow had an opposite effect in regulating EndoMT. The translational implication of the current study builds on that metformin and atorvastatin had similar effects as atheroprotective flow in suppressing the EndoMT via AMPK and SIRT1 signaling in endothelium.