Dissecting the angiogenic mechanism of pachychoroid polypoidal choroidal vasculopathy.

Polypoidal choroidal vasculopathy (PCV) is a distinct variant of neovascular age-related macular degeneration (AMD) and a major cause of vision loss in older adults, yet its pathogenesis remains poorly understood. 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-omics analyses and identified enrichment of fluid shear stress and atherosclerosis (FSS-AS) signaling pathways in this subtype. The pachychoroid phenotype, together with FSS-AS 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-cell sequencing identified the cellular origin of these angiogenic lesions and implicated endothelin-1 (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.