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The guidance receptor plexin D1 is a mechanosensor in endothelial cells
Open accessAbstract
Shear stress on arteries produced by blood flow is important for vascular development and homeostasis but can also initiate atherosclerosis 1. Endothelial cells that line the vasculature use molecular mechanosensors to directly detect shear stress profiles that will ultimately lead to atheroprotective or atherogenic responses 2. 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 structures 3-5. 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.
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“Interestingly, a recent study also reported a semaphorin-independent mechanosensitive function for Plexin-D1, a paralog of Plexin-B1, to detect blood flow shear stress in endothelial cells62.”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [62]
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Metadata
- Authors
- Mehta, V., Pang, K.-L., Rozbesky, D., Nather, K., Keen, A., Lachowski, D., Kong, Y., Karia, D., Ameismeier, M., Huang, J., Fang, Y., del Rio Hernandez, A., Reader, J. S., Jones, E. Y., & Tzima, E.
- Affiliations
- Centre for Human Genetics (GB)
- Imperial College London (GB)
- Duke University (US)
- University of Chicago (US)
- Corresponding author
- Tzima, Ellie
- ORCID
- Venue
- Nature
- Published
- 2020-02-05
- Volume
- 578
- Issue
- 7794
- Pages
- 290-295
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7025890
- OpenAlex
- W3005314662
- Cited by
- 221
- References
- 41
- Citations by year
- 2026: 25 · 2025: 42 · 2024: 39 · 2023: 31 · 2022: 41 · 2021: 27 · 2020: 16
- FWCI
- 14.34
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-05-03)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (203141/Z/16/Z, 107457/Z/15/Z, 100980, 100980/C/13/Z)
- Cancer Research UK (17721, A17721)
- British Heart Foundation (RE/13/1/30181, PG/16/29/32128)
- Medical Research Council (MR/M000141/1, MR/T000503/1)
- National Heart, Lung, and Blood Institute (R01HL136765, R01HL138223)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- PlexinD1, mechanosensing, mechanotransduction, endothelial cells, shear stress, atherosclerosis, semaphorin receptors, neuropilin-1, VEGFR2
- MeSH terms
- Animals, Female, Membrane Glycoproteins, Receptors, Cell Surface, Stress, Mechanical, Integrins, Pliability, Neuropilin-1, Semaphorins, Vascular Endothelial Growth Factor Receptor-2, Mechanotransduction, Cellular, Endothelial Cells, Intracellular Signaling Peptides and Proteins, Atherosclerosis, Mice
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