MP89-01 VASOHIBIN-1 IS A NOVEL THERAPEUTIC TARGET FOR DIABETIC ERECTILE DYSFUNCTION IN MICE

INTRODUCTION AND OBJECTIVES: Induction of neovascularization is a promising strategy to treat diabetic erectile dysfunction (ED). Here we for the first time report the unexpected role of vasohibin-1, which is previously defined as an anti-angiogenic factor, in the restoration of erectile function by enhancing cavernous angiogenesis in an animal model of diabetic ED. METHODS: Diabetes was induced by intraperitoneal injection of streptozotocin into 8-week-old C57BL/6 male mice. At 8 weeks after the induction of diabetes, the animals were divided into 4 groups: controls, streptozotocin-induced diabetic mice receiving repeated intracavernous injections of PBS (days -3 and 0; 20 mL), or vasohibin-1 protein (days -3 and 0; 1 mg and 4 mg in 20 mL of PBS, respectively). Two weeks after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested for histologic and biochemical studies. RESULTS: The cavernous expression of vasohibin-1 was down-regulated in diabetic mice and in patients with diabetic ED; vasohibin-1 was mainly expressed in endothelial cells. Vasohibin-1 knockout mice revealed decrease in cavernous endothelial and pericyte content compared with wild type mice, which resulted in deterioration of erectile function. Local delivery of vasohibin-1 into the corpus cavernosum of diabetic mice induced significant restoration of erectile function, which reached up to 85% of control values at the concentration of 4 mg/20 mL. Vasohibin-1 significantly increased cavernous endothelial cell and induced eNOS phosphorylation (Ser1177). Vasohibin-1 decreased extravasation of oxidized-LDL by restoring pericyte content and endothelial cell-cell junction proteins in the diabetic mice. By using proteome profiler array kit, we found that the induction of angiogenic factors, including angiopoietin-1, vascular endothelial growth factor, and basic fibroblasts growth factor, mainly in fibroblasts is a major molecular mechanism responsible for vasohibin1-mediated cavernous angiogenesis and subsequent restoration of erectile function. CONCLUSIONS: Our findings suggest that vasohibin-1 is proangiogenic in diabetic penis and is a promising therapeutic target for ED from vascular causes.