Selective Suppression of Pathological, but Not Physiological, Retinal Neovascularization by Blocking Angiotensin II Type 1 Receptor

Abstract

Abstract: : Purpose: To investigate the anti–inflammatory and anti–angiogenic effects of telmisartan, an angiotensin II type 1 receptor (AT1–R) antagonist, on ischemia–induced retinal neovascularization. Methods: C57BL/6 neonatal mice were reared in 80% concentration of oxygen from postnatal (P) day 7–12, followed by room–air breeding to P17 to induce ischemia–initiated retinal neovascularization (i.e. a murine model of ischemic retinopathy). Animals received intraperitoneal injection of telmisartan or vehicle daily from P12 to P17. Tissue localization of AT1–R was examined by immunohistochemistry for murine retinal whole–mounts and human fibrovascular tissues excised at vitrectomy for proliferative diabetic retinopathy. Concanavalin A lectin perfusion–labeling technique was utilized to evaluate the areas of physiological and pathological retinal new vessels and the number of leukocytes adhering to the vasculature. Retinal mRNA and protein levels of intercellular adhesion molecule–1 (ICAM–1), vascular endothelial growth factor receptor–1 (VEGFR–1), and VEGFR–2 were examined by reverse transcription–polymerase chain reaction (RT–PCR) and enzyme–linked immunosorbent assay (ELISA). Results: Vessels in human fibrovascular tissues as well as murine retinas were positive for AT1–R. Pathological (P < 0.01), but not physiological, retinal neovascularization was significantly suppressed in telmisartan–treated ischemic retinopathy mice compared with vehicle–treated ischemic retinopathy animals. The area ratio of pathological neovascularization in the telmisartan group was 3.2 %, which was significantly (P < 0.01) decreased compared to the vehicle group (9.7 %). The number of adherent leukocytes in ischemic retinopathy (57.8 / retina) was significantly (P < 0.01) higher than normal P17 mice. Leukocyte counts showed a significant (P < 0.01) decrease in the telmisartan group (21.3 / retina), compared with the vehicle group (53.7 / retina). Retinal ICAM–1 and VEGFR–1 levels in the temisartan–treated group were significantly lower than in vehicle–treated group. No statistical difference was detected in retinal VEGFR–2 levels between the two groups. Conclusions: The current study suggests that AT1–R signaling blockade leads to the selective suppression of pathological, but not physiological, retinal neovascularization via the inhibition of the inflammatory processes related to the pathological neovascularization.

Keywords: drug toxicity/drug effects • ischemia • retinopathy of prematurity