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The potential for fibrosis across most organ systems may stem from its connections to wound healing and the ubiquitous presence of vascular endothelium. Endothelial cells (ECs) and angiogenesis, cells and associated biological program central to wound healing, have been heavily implicated in many organ-specific fibroses, but the relationship between angiogenesis and fibrogenesis remains debated and little has been established in terms of how the EC phenotype governs tissue healing vs. fibrosis. Here, we examine a murine lung injury model enabling EC lineage tracing and observe the invasion of aberrant ECs from the bronchial microvasculature following lung injury along with concurrent densification of matrix fibers surrounding these vessels. To investigate the underlying mechanisms governing their appearance, we established a microphysiological system (MPS) of arteriole\/venule-scale microvessels embedded within a tunable stromal mimetic matrix and find that heightened extracellular matrix fiber density activates ECs, drives endothelial to mesenchymal transition, and promotes aberrant tip EC (ATEC) invasion into the matrix. ATECs remain adherent to fibrotic matrix and possess a pro-inflammatory phenotype that secretes TGF-\u03b22. Notably, our studies establish that the formation of ATECs is gated by destabilization of endothelial adherens junction upon EC adhesion to fibrous matrix, and associated regulation of TGF-\u03b2 signaling that is mediated by a novel VE-cadherin \u2013 TGF-\u03b2R2 axis. The current lack of effective anti-fibrotic therapies suggests potential critical involvement of other cell types such as ECs, and our findings suggest new contributions of ECs to fibrotic progression that may better inform future targets for novel anti-fibrotic therapeutics.<\/jats:p>","DOI":"10.1101\/2025.05.20.655215","type":"posted-content","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T11:55:15Z","timestamp":1748174115000},"source":"Crossref","is-referenced-by-count":2,"title":["Perivascular matrix densification dysregulates angiogenesis and activates pro-inflammatory endothelial cells"],"prefix":"10.64898","author":[{"given":"Jingyi","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering University of Michigan, Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Y.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of 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