AB088. Inhibition of prongf pathway restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

BACKGROUND: Patients with diabetic erectile dysfunction (ED) usually respond poorly to oral phosphodiesterase-5 inhibitors due to a lack of bioavailable nitric oxide from severe endothelial and neural dysfunction. ProNGF and its receptor p75(NTR) are known to be up-regulated in diabetic condition and to play important role in triggering neuronal survival and vascular cells apoptosis. The aim of this study was to investigate the role of proNGF/p75(NTR) signal pathway and the effectiveness of proNGF neutralizing antibody (proNGF-Ab) in restoring erectile function in streptozotocin-induced diabetic mouse. METHODS: Diabetes mellitus was induced by intraperitoneal injection of streptozotocin (50 mg/kg) into 8-week-old C57BL/6 male mice for 5 consecutive days. At 8 weeks after the induction of diabetes mellitus, the animals were distributed into 3 groups: controls, streptozotocin-induced diabetic mice receiving repeated intracavernous injections of saline (days −3 and 0; 20 µL) or proNGF-Ab (days −3 and 0; 20 µg in 20 µL of saline). We measured erectile function by electrical stimulation of the cavernous nerve at 2 weeks after treatment. The penis then was harvested for histological and biochemical studies. We also examined the effect of proNGF-Ab and p75(NTR) siRNA in primary cultured mouse cavernous endothelial cells, pericytes and major pelvic ganglion. RESULTS: The cavernous expression of proNGF and p75(NTR) was up-regulated in diabetic patients and STZ-induced diabetic mouse. Intracavernous injection of proNGF-Ab successfully restored erectile function in diabetic mice, which reach up to 90–100% of control values. ProNGF-Ab significantly increased cavernous endothelial cell content, pericytes content and endothelial cell-cell junction proteins; and restored neuronal cell content in the cavernous tissue of diabetic mice. Under the high glucose condition, proNGF-Ab and p75(NTR) siRNA also promoted tube formation in mouse cavernous endothelial cells and pericytes; decreased the apoptosis of endothelial cells and pericytes; and enhanced neurite sprouting in major pelvic ganglion culture. CONCLUSIONS: Our findings suggest that inhibition of proNGF/p75(NTR) signal pathway is a promising therapeutic strategy for diabetic ED.