Endothelin 2-Mediated Neuroinflammation Drives Hypertensive Retinal Dysfunction
Yingkun Cui, Man-Ting Au, Lanlan Zhang, Ting Zhang, Li Pan, Hoi-Lam Li, Yuqi Zhang, Margaret MH Wu, Huan Li, Shing-Yan Roy Chung, Kangyi Yang, Pan Feng, Chunyi Wen, Chi-Wai DoBACKGROUND:
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
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.