Synthetic angiopoietin-1 variant rescues erectile function through healthy cavernous angiogenesis in a hypercholesterolemic mouse

초록

Objectives: Neovascularization is a promising strategy for curing erectile dysfunction (ED). The aim of this study was to determine the effectiveness of the soluble, stable, and potent Angiopoietin-1 (Ang1) variant, COMP-Ang1, in promoting cavernous angiogenesis and restoring erectile function in a mouse model of hypercholesterolemic ED. Methods: Two-month-old male C57BL/6J mice were used and hypercholesteromia was induced by feeding a diet containing 4% cholesterol and 1% cholic acid for 3 months. The animals were distributed into 6 groups: controls, hypercholesterolemic mice, and hypercholesterolemic mice receiving a single intracavernous injection of ad-LacZ or ad-COMP-Ang1 and repeated injections of BSA or COMP-Ang1 recombinant protein. Results: Local delivery of the COMP-Ang1 into the penises of hypercholesterolemic mice increased cavernous angiogenesis, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function up to 8 weeks after treatment. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished in eNOS-knockout mice and in the presence of the NOS inhibitor, L-NAME. COMP-Ang1 also restored the integrity of endothelial cell-cell junction by down-regulating the expression of histone deacetylase 2 in primary cultured mouse cavernous endothelial cells. Conclusions: These findings constitute a new paradigm toward curative treatment of both cavernous angiopathy and ED.