Journal
SCIENCE ADVANCES
Volume 7, Issue 28, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg5060
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Funding
- Wellcome Trust [203141/Z/16/Z]
- BHF [PG/16/29/32128, PG/19/70/34630, RG/F/20/110025]
- John Fell Fund
- BHF Centre of Excellence, Oxford [RE/13/1/30181]
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The response of endothelial cells to mechanical forces plays a critical role in vascular health, and vascular pathologies may lead to endothelial-to-mesenchymal transition. This study identifies a unique mechanoreceptor, Alk5, and an Alk5-Shc pathway that are crucial for EndMT and atherosclerosis.
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.
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