The guidance receptor plexin D1 is a mechanosensor in endothelial cells

Vedanta Mehta, Kar-Lai Pang, Daniel Rozbesky, Katrin Nather, Adam Keen, Dariusz Lachowski, Youxin Kong, Dimple Karia, Michael Ameismeier, Jianhua Huang, Yun Fang, Armando Rio Hernandez, John S. Reader, E. Yvonne Jones and Ellie Tzima ()
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Vedanta Mehta: University of Oxford
Kar-Lai Pang: University of Oxford
Daniel Rozbesky: University of Oxford
Katrin Nather: University of Oxford
Adam Keen: University of Oxford
Dariusz Lachowski: Imperial College London
Youxin Kong: University of Oxford
Dimple Karia: University of Oxford
Michael Ameismeier: University of Oxford
Jianhua Huang: Duke University
Yun Fang: University of Chicago
Armando Rio Hernandez: Imperial College London
John S. Reader: University of Oxford
E. Yvonne Jones: University of Oxford
Ellie Tzima: University of Oxford

Nature, 2020, vol. 578, issue 7794, 290-295

Abstract: Abstract Shear stress on arteries produced by blood flow is important for vascular development and homeostasis but can also initiate atherosclerosis1. Endothelial cells that line the vasculature use molecular mechanosensors to directly detect shear stress profiles that will ultimately lead to atheroprotective or atherogenic responses2. Plexins are key cell-surface receptors of the semaphorin family of cell-guidance signalling proteins and can regulate cellular patterning by modulating the cytoskeleton and focal adhesion structures3–5. However, a role for plexin proteins in mechanotransduction has not been examined. Here we show that plexin D1 (PLXND1) has a role in mechanosensation and mechanically induced disease pathogenesis. PLXND1 is required for the response of endothelial cells to shear stress in vitro and in vivo and regulates the site-specific distribution of atherosclerotic lesions. In endothelial cells, PLXND1 is a direct force sensor and forms a mechanocomplex with neuropilin-1 and VEGFR2 that is necessary and sufficient for conferring mechanosensitivity upstream of the junctional complex and integrins. PLXND1 achieves its binary functions as either a ligand or a force receptor by adopting two distinct molecular conformations. Our results establish a previously undescribed mechanosensor in endothelial cells that regulates cardiovascular pathophysiology, and provide a mechanism by which a single receptor can exhibit a binary biochemical nature.

Date: 2020
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DOI: 10.1038/s41586-020-1979-4

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