Abstract
Blood flow influences atherosclerosis by generating wall shear stress, which alters endothelial cell (EC) physiology. Low shear stress induces dedifferentiation of EC through a process termed endothelial-to-mesenchymal transition (EndMT). The mechanisms underlying shear stress-regulation of EndMT are uncertain. Here we investigated the role of the transcription factor Snail in low shear stress-induced EndMT. Studies of cultured EC exposed to flow revealed that low shear stress induced Snail expression. Using gene silencing it was demonstrated that Snail positively regulated the expression of EndMT markers (Slug, N-cadherin, α-SMA) in EC exposed to low shear stress. Gene silencing also revealed that Snail enhanced the permeability of endothelial monolayers to macromolecules by promoting EC proliferation and migration. En face staining of the murine aorta or carotid arteries modified with flow-altering cuffs demonstrated that Snail was expressed preferentially at low shear stress sites that are predisposed to atherosclerosis. Snail was also expressed in EC overlying atherosclerotic plaques in coronary arteries from patients with ischemic heart disease implying a role in human arterial disease. We conclude that Snail is an essential driver of EndMT under low shear stress conditions and may promote early atherogenesis by enhancing vascular permeability.
Highlights
Blood flow influences atherosclerosis by generating wall shear stress, which alters endothelial cell (EC) physiology
To determine whether shear stress regulates the expression of mesenchymal genes we exposed cultured EC to flow. qPCR revealed that the expression of several mesenchymal markers (Snail, Slug, N-cadherin and αSMA) was elevated in Human umbilical vein EC (HUVEC) exposed to low, oscillatory shear compared to high shear stress using a parallel plate apparatus (Fig. 1a)
These data lead us to conclude that VE-cadherin expression was not reduced in EC exposed to low shear stress despite their acquisition of mesenchymal markers suggesting that the EC transition towards a mesenchymal state was partial
Summary
Blood flow influences atherosclerosis by generating wall shear stress, which alters endothelial cell (EC) physiology. Studies of cultured EC exposed to flow revealed that low shear stress induced Snail expression. Endothelial-to-mesenchymal transition (EndMT) is characterised by multiple morphological and physiological changes including loss of cell polarity, disruption of intercellular junctions, increased proliferation, delamination and migration of cells into surrounding tissue[1, 2]. This process is essential for atrioventricular valve formation where EC expressing mesenchymal markers invade the cardiac jelly to form a cardiac cushion which subsequently forms the valves[3]. We recently demonstrated that low shear stress promotes EndMT via activation of the transcription factors GATA4 and TWIST19. We used cultured EC exposed to flow and animal models with varying levels of flow to demonstrate that Snail plays an essential role in the induction of EndMT in response to disturbed flow
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
