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Despite the established link between CKD and cardiovascular disease, the role of uremic toxins in monocyte\u2010endothelial interactions under hypertensive conditions remains underexplored. Here, a 3D microfluidic model is developed to examine the effects of indoxyl sulfate on monocyte adhesion and extravasation across engineered microvessels embedded in hydrogels with different densities under controlled luminal pressure. Elevated pressure alone in absence of indoxyl sulfate significantly enhanced monocyte adhesion and extravasation, regardless of matrix density, while matrix density regulated adhesion and transmigration in the uremic environment. ICAM\u20101 is identified as a key driver of THP\u20101 monocyte adhesion to the endothelium. Additionally, denser hydrogels primed monocytes toward a pro\u2010inflammatory phenotype with reduced phagocytic capacity, while softer hydrogels induced an anti\u2010inflammatory\u2010like phenotype with enhanced phagocytosis. However, the uremic environment reduced phagocytosis and shifted cells toward a pro\u2010inflammatory\u2010like state, irrespective of matrix density. This approach has the potential to dissect multiple factors that contribute to elevated cardiovascular risks in CKD patients and improve the understanding of mechanisms involved in monocyte dynamics in CKD\u2010related cardiovascular disease.<\/jats:p>","DOI":"10.1002\/advs.202417091","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T03:39:59Z","timestamp":1750390799000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Microphysiological Uremia Model Reveals Biophysical Potentiators of Vascular Dysfunction"],"prefix":"10.1002","volume":"12","author":[{"given":"Mitesh","family":"Rathod","sequence":"first","affiliation":[{"name":"Lampe Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University  10010 Mary Ellen Jones Building, 116 Manning Drive Chapel Hill NC 27514 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116 Manning Drive Chapel Hill NC 27514 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Meehan","sequence":"additional","affiliation":[{"name":"Lampe Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University  10010 Mary Ellen Jones Building, 116 Manning Drive Chapel Hill NC 27514 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabir","family":"Roy\u2010Chaudhury","sequence":"additional","affiliation":[{"name":"WG (Bill) Hefner Salisbury VA Medical Center  1601 Brenner Ave Salisbury NC 28144 USA"},{"name":"UNC Kidney Center University of North Carolina at Chapel Hill School of Medicine  7204 Burnett\u2010Womack Chapel Hill NC 27599 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2728-0746","authenticated-orcid":false,"given":"William J.","family":"Polacheck","sequence":"additional","affiliation":[{"name":"Lampe 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