Endothelin 2–Mediated Neuroinflammation Drives Hypertension-Associated Retinal Dysfunction

Abstract Systemic hypertension is a significant risk factor for glaucoma, a leading cause of irreversible blindness, yet the mechanistic basis connecting the two conditions remains elusive. Here, we demonstrate that hypertensive rats develop accelerated retinal degeneration characterized by retinal thinning, functional impairment, reduced perfusion, and progressive neuroinflammation. Critically, these changes occur despite persistently lower intraocular pressure (IOP), indicating an IOP-independent mechanism of pathology. Transcriptomic and biochemical analyses identified a robust activation of the retinal endothelin system, with endothelin-2 (EDN2) being the earliest and most significantly upregulated component. AAV-delivered retinal Edn2 knockdown completely restored retinal function, ameliorated neuroinflammation, and enhanced retinal blood flow in hypertensive rats. Pharmacological blockade of endothelin receptor type A (EDNRA), but not type B, replicated these protective effects without altering IOP. Our findings establish EDN2 as a central, IOP-independent driver of hypertension-associated retinal neurodegeneration and identify the endothelin-EDNRA axis as a potential therapeutic target to prevent vision loss in hypertensive patients.