Matrix-associated extracellular vesicles modulate smooth muscle cell adhesion and directionality by presenting collagen VI

Abstract The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, can invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis. Here we show that FN stimulates VSMCs to secrete small extracellular vesicles (sEVs) by activating the β1 integrin/FAK/Src pathway as well as Arp2/3-dependent branching of the actin cytoskeleton. We found that sEVs are trapped by the ECM in vitro and colocalise with FN in symptomatic atherosclerotic plaques in vivo. Functionally, ECM-trapped sEVs induced the formation of focal adhesions (FA) with enhanced pulling forces at the cellular periphery preventing cellular spreading and adhesion. Proteomic and GO pathway analysis revealed that VSMC-derived sEVs display a cell adhesion signature and are specifically enriched with collagen VI on the sEV surface. In vitro assays identified collagen VI as playing a key role in cell adhesion and invasion directionality. Taken together our data suggests that the accumulation of FN is a key early event in vessel repair acting to promote secretion of collage VI enriched sEVs by VSMCs. These sEVs stimulate directional invasion, most likely by triggering peripheral focal adhesion formation and actomyosin contraction to exert sufficient traction force to enable VSMC movement within the complex vascular ECM network.

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Published
2025-09-05
DOI
https://doi.org/10.7554/elife.90375.2
Primary Topic
Extracellular vesicles in disease
Type
article
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article

Matrix-associated extracellular vesicles modulate smooth muscle cell adhesion and directionality by presenting collagen VI

Martin James Humphries, Derek Warren, Dylan M. Owen, Mark Holt et al.
Extracellular vesicles in disease
article

Matrix-associated extracellular vesicles modulate smooth muscle cell adhesion and directionality by presenting collagen VI

Martin James Humphries, Derek Warren, Dylan M. Owen, Mark Holt, Alexander N. Kapustin, Kseniya Rubina, Chris Molenaar, George Chennell, Simona Zingaro, Meredith Whitehead, Maxim Sinitsky, Richard E. Cheney, Maddy Parsons, Sofia Serena Tsakali, Anton G. Kutikhin, Sadia Ahmad, D. Michiel Pegtel, Catherine M. Shanahan, Arseniy Lobov, Frederik J. Verweij, Thomas Iskratsch, Aled Clayton, Bozhana Zainullina, Mengying Wu, Leo Bogdanov, Yu Chen
article en

Abstract

Abstract The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, can invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis. Here we show that FN stimulates VSMCs to secrete small extracellular vesicles (sEVs) by activating the β1 integrin/FAK/Src pathway as well as Arp2/3-dependent branching of the actin cytoskeleton. We found that sEVs are trapped by the ECM in vitro and colocalise with FN in symptomatic atherosclerotic plaques in vivo. Functionally, ECM-trapped sEVs induced the formation of focal adhesions (FA) with enhanced pulling forces at the cellular periphery preventing cellular spreading and adhesion. Proteomic and GO pathway analysis revealed that VSMC-derived sEVs display a cell adhesion signature and are specifically enriched with collagen VI on the sEV surface. In vitro assays identified collagen VI as playing a key role in cell adhesion and invasion directionality. Taken together our data suggests that the accumulation of FN is a key early event in vessel repair acting to promote secretion of collage VI enriched sEVs by VSMCs. These sEVs stimulate directional invasion, most likely by triggering peripheral focal adhesion formation and actomyosin contraction to exert sufficient traction force to enable VSMC movement within the complex vascular ECM network.

University of East Anglia (GB), University of North Carolina at Chapel Hill (US), Queen Mary University of London (GB), Morpho (United States) (US), King's College London (GB), Utrecht University (NL), Lomonosov Moscow State University (RU), Norwich Research Park (GB), Manchester Academic Health Science Centre (GB), Wellcome Centre for Cell-Matrix Research (GB), University of Manchester (GB), Institute of Cytology (RU), Institute of Immunology (HR), Moscow State University (TJ), Kemerovo State University (RU), Cardiff University (GB), University of Birmingham (GB), Vrije Universiteit Amsterdam (NL)
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Extracellular vesicles in disease
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