02132nas a2200349   4500000000100000008004100001260001500042100002400057700002700081700003000108700002100138700002500159700001900184700002100203700001900224700001900243700002500262700001400287700001700301700001900318700002400337700001800361700001600379700002200395700002100417700002300438245011000461856005500571300001300626490000700639520113600646       2025                            d  c2025-01-101 aCristiane M. Franca1 aMaria Elisa Lima Verde1 aAlice Corrêa Silva-Sousa1 aAmin Mansoorifar1 aAvathamsa Athirasala1 aRamesh Subbiah1 aAnthony Tahayeri1 aMauricio Sousa1 aMay Anny Fraga1 aRahul M. Visalakshan1 aAaron Doe1 aKeith Beadle1 aMcKenna Finley1 aEmilios Dimitriadis1 aJennifer Bays1 aMarina Uroz1 aKenneth M. Yamada1 aChristopher Chen1 aLuiz E. Bertassoni00aPerivascular cells function as key mediators of mechanical and structural changes in vascular capillaries  uhttps://www.science.org/doi/10.1126/sciadv.adp3789  aeadp37890 v113 aA hallmark of chronic and inflammatory diseases is the formation of a fibrotic and stiff extracellular matrix (ECM), typically associated with abnormal, leaky microvascular capillaries. Mechanisms explaining how the microvasculature responds to ECM alterations remain unknown. Here, we used a microphysiological model of capillaries on a chip mimicking the characteristics of healthy or fibrotic collagen to test the hypothesis that perivascular cells mediate the response of vascular capillaries to mechanical and structural changes in the human ECM. Capillaries engineered in altered fibrotic collagen had abnormal migration of perivascular cells, reduced pericyte differentiation, increased leakage, and higher regulation of inflammatory/remodeling genes, all regulated via NOTCH3, a known mediator of endothelial-perivascular cell communication. Capillaries engineered either with endothelial cells alone or with perivascular cells silenced for NOTCH3 expression showed a minimal response to ECM alterations. These findings reveal a previously unknown mechanism of vascular response to changes in the ECM in health and disease.