Mechanical forces regulate endothelial-to-mesenchymal transition and atherosclerosis via an Alk5-Shc mechanotransduction pathway.

Vedanta Mehta,Zhongming Chen,Ellie Tzima,Kar-Lai Pang,Daniel T Sweet,Jianhua Huang,Christopher S Givens,Hanjoong Jo,John S Reader

doi:10.1126/sciadv.abg5060

Abstract

The response of endothelial cells to mechanical forces is a critical determinant of vascular health. Vascular pathologies, such as atherosclerosis, characterized by abnormal mechanical forces are frequently accompanied by endothelial-to-mesenchymal transition (EndMT). However, how forces affect the mechanotransduction pathways controlling cellular plasticity, inflammation, and, ultimately, vessel pathology is poorly understood. Here, we identify a mechanoreceptor that is sui generis for EndMT and unveil a molecular Alk5-Shc pathway that leads to EndMT and atherosclerosis. Depletion of Alk5 abrogates shear stress-induced EndMT responses, and genetic targeting of endothelial Shc reduces EndMT and atherosclerosis in areas of disturbed flow. Tensional force and reconstitution experiments reveal a mechanosensory function for Alk5 in EndMT signaling that is unique and independent of other mechanosensors. Our findings are of fundamental importance for understanding how mechanical forces regulate biochemical signaling, cell plasticity, and vascular disease.

Highlights

Mechanical forces in the vascular system are critical determinants of homeostasis but can be instigators of disease [1]
We hypothesized that Alk5 plays a role in endothelial-to-mesenchymal transition (EndMT) induced by shear stress and adopted a loss-of-function approach by small interfering RNA–mediated transfection to test the role of Alk5 in the endothelium
We subjected endothelial cell (EC) transfected with control and Alk5 small interfering RNA (siRNA) to acute shear stress [which elicits the same sustained signaling observed with chronic disturbed shear stress [1]] and examined phosphorylation of Smad2

Summary

Introduction

Mechanical forces in the vascular system are critical determinants of homeostasis but can be instigators of disease [1]. The TGF -Alk pathway is important for the shear stress response [15,16,17], and recent work has shown that endothelial-specific deletion of both TGF R1 (Alk5) and TGF R2 delayed atherosclerotic plaque growth and induced regression of fully established lesions, clearly establishing a causal relationship between EndMT and atherosclerosis [18]. This body of work gives credence to the idea that disturbed shear stress promotes EndMT and contributes to atherogenesis; the mechanoreceptor responsible for flow-induced EndMT remains undiscovered. A direct connection between force, mechanosensing, and EndMT signaling, which regulates cellular plasticity, has never been demonstrated

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Results

Conclusion