Endothelin 2-Mediated Neuroinflammation Drives Hypertensive Retinal Dysfunction

BACKGROUND: Systemic hypertension is a risk factor for glaucoma, a leading cause of irreversible blindness, yet the mechanistic basis connecting the 2 conditions remains elusive. METHODS: A longitudinal assessment of blood pressure, intraocular pressure, retinal function, structure, and perfusion was conducted in spontaneously hypertensive rats and Wistar-Kyoto rats. Transcriptomic analyses and immunofluorescence staining were performed to investigate hypertension-associated retinal biochemical changes. AAV-mediated knockdown of endothelin 2 was used to investigate its mechanistic role. RESULTS: Hypertensive rats develop accelerated retinal degeneration marked by retinal thinning, functional impairment, reduced perfusion, and progressive neuroinflammation. Critically, these changes occur despite persistently low intraocular pressure, indicating an intraocular pressure-independent mechanism underlying the pathology. Biochemical analyses identified robust activation of the retinal endothelin system, with endothelin 2 the most significantly upregulated component. AAV-mediated retinal endothelin 2 knockdown substantially restored retinal function, ameliorated neuroinflammation, and enhanced retinal blood flow in hypertensive rats. Pharmacological blockade of endothelin receptor type A, but not type B, replicated these protective effects without altering intraocular pressure. CONCLUSIONS: Our findings establish endothelin 2 as an important, intraocular pressure-independent contributing factor to hypertension-associated retinal neurodegeneration and identify the endothelin-endothelin receptor type A axis as a potential therapeutic target to prevent vision loss in patients with hypertension.