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

• Type of Material: Article
• Authors: Vedanta Mehta, University of Oxford; Kar-Lai Pang, University of Oxford; Christopher S Givens, University of North Carolina; Zhongming Chen, University of North Carolina; Jianhua Huang, University of North Carolina; Daniel T Sweet, University of North Carolina; Hanjoong Jo, Emory University; John S Reader, University of Oxford; Ellie Tzima, University of Oxford
• Language: English
• Date: 2021-07-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abg5060
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 7
• Issue: 28
• Grant/Funding Information: This work was supported, in part, by grants from the Wellcome Trust (senior research fellowship to E.T.); BHF (PG/16/29/32128, PG/19/70/34630, and RG/F/20/110025 to E.T.); John Fell Fund (to E.T.); the BHF Centre of Excellence, Oxford (RE/13/1/30181); and the Wellcome Trust grant 203141/Z/16/Z supporting the Wellcome Centre for Human Genetics. pcDNA3-Alk5wt was a gift from A. Moustakas (Addgene plasmid no. 80876). PECAM-1 antibody used for tensional force application experiments was a gift from P. Newman and D. Newman.
• Keywords: FLOW; INFLAMMATION; Multidisciplinary Sciences; CELLS; Science & Technology; Science & Technology - Other Topics; PECAM-1
• Research Categories: Engineering, Biomedical

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.