HP-01-005 Effectiveness of intracavernous delivery of recombinant human hepatocyte growth factor on erectile function in the streptozotocin-induced diabetic mouse

Abstract

Diabetic erectile dysfunction (ED) is a disease mostly of vascular origin with severe endothelial dysfunction and responds poorly to oral phosphodiesterase-5 inhibitors. Hepatocyte growth factor (HGF) is a pleiotropic factor that plays an essential role in the regulation of cell proliferation, survival, and angiogenesis. Here, we determined the effectiveness of recombinant human hepatocyte growth factor (rh-HGF) protein in restoring erectile function in diabetic mice. Intracavernous injections of phosphate-buffered saline (days -3 and 0; 20 μL), a single intracavernous injection of rh-HGF protein (day 0; 4.2 μg/20 μL of PBS), or two successive intracavernous injections of rh-HGF protein (days -3 and 0; 4.2 μg/20 μL, respectively). Two weeks after the treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested for histologic and biochemical studies. Repeated intracavernous injections of rh-HGF protein induced significant restoration of erectile function in diabetic mice (90% of control values), whereas a single intracavernous injection of rh-HGF protein elicited modest improvement. Rh-HGF significantly increased the content of endothelial cells, pericytes, and smooth muscle cells and decreased the generation of reactive oxygen species (superoxide anion and peroxynitrite) and extravasation of oxidized LDL in diabetic mice. Rh-HGF protein promoted proliferation and decreased apoptosis in primary cultured mouse cavernous endothelial cells and pericytes in vitro. Under high-glucose condition, rh-HGF protein also promoted tube formation in MCECs and enhanced neurite sprouting in MPG culture in vitro.