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Upon exposure to pathological stimuli, they can take on alternative phenotypes that, among others, have been described as macrophage like, or foam cells. VSMC foam cells make up &gt;50% of all arterial foam cells and have been suggested to retain an even higher proportion of the cell stored lipid droplets, further leading to apoptosis, secondary necrosis, and an inflammatory response. However, the mechanism of VSMC foam cell formation is still unclear. Here, it is identified that mechanical stimulation through hypertensive pressure alone is sufficient for the phenotypic switch. Hyperspectral stimulated Raman scattering imaging demonstrates rapid lipid droplet formation and changes to lipid metabolism and changes are confirmed in ABCA1, KLF4, LDLR, and CD68 expression, cell proliferation, and migration. Further, a mechanosignaling route is identified involving Piezo1, phospholipid, and arachidonic acid signaling, as well as epigenetic regulation, whereby CUT&amp;Tag epigenomic analysis confirms changes in the cells (lipid) metabolism and atherosclerotic pathways. Overall, the results show for the first time that VSMC foam cell formation can be triggered by mechanical stimulation alone, suggesting modulation of mechanosignaling can be harnessed as potential therapeutic strategy.<\/jats:p>","DOI":"10.1002\/advs.202308686","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T22:49:23Z","timestamp":1703544563000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells"],"prefix":"10.1002","volume":"11","author":[{"given":"Pamela","family":"Swiatlowska","sequence":"first","affiliation":[{"name":"School of Engineering and Materials Science Queen Mary University of London  London E1 4NS UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Tipping","sequence":"additional","affiliation":[{"name":"Department of Pure and Applied Chemistry University of Strathclyde  Glasgow G1 1QA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Marhuenda","sequence":"additional","affiliation":[{"name":"School of Engineering and Materials Science Queen Mary University of London  London E1 4NS UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Severi","sequence":"additional","affiliation":[{"name":"School of Engineering and Materials Science Queen Mary University of London  London E1 4NS UK"},{"name":"Department of Translational Medicine Laboratory for Technologies of Advanced Therapies (LTTA) University of Ferrara  Ferrara 44121 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitalay","family":"Fomin","sequence":"additional","affiliation":[{"name":"Y.ai  New York 10037 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhisheng","family":"Yang","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute Queen Mary University of London  London EC1M 6BQ UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingzhong","family":"Xiao","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute Queen Mary University of London  London EC1M 6BQ UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Pure and Applied Chemistry University of Strathclyde  Glasgow G1 1QA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Shanahan","sequence":"additional","affiliation":[{"name":"School of Cardiovascular Medicine and Sciences King's College London  London SE5 9NU UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3738-7830","authenticated-orcid":false,"given":"Thomas","family":"Iskratsch","sequence":"additional","affiliation":[{"name":"School of Engineering and Materials Science Queen Mary University of London  London E1 4NS UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,25]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0227-9"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.23.17661"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1990.tb42313.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410075200"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.7.937"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)42250-3"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000131260.80316.37"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.112.000810"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.005015"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.312434"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.121.316600"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3866"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3903"},{"key":"e_1_2_8_14_1","first-page":"1867","volume":"118436","author":"Ward M.","year":"2020","journal-title":"Biochim. 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