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Pachychoroid PCV is a subtype characterized by poor treatment response, minimal typical AMD features, and dilated choroidal vessels. Using a multicenter PCV cohort, we conducted plasma multi\u2010omics analyses and identified enrichment of fluid shear stress and atherosclerosis (FSS\u2010AS) signaling pathways in this subtype. The pachychoroid phenotype, together with FSS\u2010AS enrichment, implicated altered choroidal hemodynamics in its pathogenesis. By inducing choroidal circulatory hypertension (CCH) in mice, we recapitulated, for the first time, the hallmark ocular lesions of pachychoroid PCV. Single\u2010cell sequencing identified the cellular origin of these angiogenic lesions and implicated endothelin\u20101 (EDN1) as a key effector. Alleviating choroidal hypertension, reducing EDN1 expression, or pharmacologically blocking the endothelin receptor A (EDNRA, the receptor for EDN1), prevented lesion formation. In vitro, disturbed fluid shear stress upregulated EDN1 in choroidal endothelial cells and promoted pathological remodeling and angiogenesis through EDNRA. Collectively, our findings define a pathogenic cascade wherein CCH induces abnormal hemodynamics (disrupted fluid shear stress) and drives angiogenesis via the EDN1\/EDNRA axis, offering mechanistic insight and identifying a potential therapeutic target for pachychoroid PCV.<\/jats:p>","DOI":"10.1002\/imt2.70176","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:07:11Z","timestamp":1790777231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dissecting the angiogenic mechanism of pachychoroid polypoidal choroidal vasculopathy"],"prefix":"10.1002","author":[{"given":"Xinyu","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"},{"name":"Beijing Key Laboratory of Fundus Diseases Intelligent Diagnosis &amp; Drug\/Device 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