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Although endothelial dysfunction is increasingly recognized as a key contributor to fibrogenesis, the intracellular signaling pathways that couple inflammatory cues to endothelial\u2013immune interactions remain incompletely defined. Ras\u2010related protein Rap2a (RAP2A), a small GTPase implicated in stress and inflammatory signaling, has not been systematically investigated in pulmonary endothelial cells during fibrotic lung injury. Here, using a bleomycin\u2010induced experimental lung fibrosis model, we observed that RAP2A expression was markedly upregulated in pulmonary endothelial cells and correlated with disease severity. Endothelium\u2010enriched knockdown of Rap2a via AAV9\u2010Cdh5\u2010shRNA attenuated inflammatory cell adhesion to the pulmonary endothelium, reduced fibrotic remodeling, and improved lung function. Mechanistically, RAP2A promoted endothelial activation by enhancing MAP4K4\u2010dependent signaling and upregulating vascular cell adhesion molecule 1 (VCAM1) in response to pro\u2010inflammatory stimulation, thereby facilitating leukocyte\u2013endothelial interactions. In vitro assays further demonstrated that RAP2A deficiency impaired tumor necrosis factor\u2010\u03b1\u2013induced endothelial adhesiveness without affecting basal endothelial integrity. Collectively, our findings identify endothelial RAP2A as a regulator of inflammatory endothelial activation in experimental lung fibrosis and suggest that targeting RAP2A\u2010mediated signaling may represent a potential strategy to modulate endothelial\u2013immune crosstalk during fibrotic lung injury.<\/jats:p>","DOI":"10.1002\/advs.202519892","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T19:13:32Z","timestamp":1770837212000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inactivation\n                    <i>Rap2a<\/i>\n                    in Endothelial Cell Prevents Pulmonary Fibrosis by Regulating Immune Microenvironment Through MAP4K4\u2010VCAM1 Signaling"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiaolan","family":"Zheng","sequence":"first","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE Department 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