Abstract
Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable. Recently, the link between ED and cardiovascular disease was unveiled and the main etiology of ED was found to be vasculogenic. Therefore, neovascularization is a promising strategy for curing ED. Angiopoietin-1 (Ang1) is an angiogenic growth factor that promotes the generation of stable and functional vasculature. Here, we demonstrate that local delivery of the soluble, stable, and potent Ang1 variant, COMP-Ang1 gene or protein, into the penises of hypercholesterolemic mice increases cavernous angiogenesis, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function and cavernous blood flow up to 8 weeks after treatment. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished in Nos3-/- 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 the penis of hypercholesterolemic mice and in primary cultured mouse cavernous endothelial cells. These findings constitute a new paradigm toward curative treatment of both cavernous angiopathy and ED.
Highlights
Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable
Because Ang1-induced angiogenesis appears to require the generation of nitric oxide (NO) by activated eNOS30, we determined whether endothelial nitric oxide synthase (eNOS) or NOS participated in cartilage oligomeric matrix protein (COMP)-Ang1-induced cavernous angiogenesis and subsequent restoration of erectile function using Nos3-/- mice fed a high-cholesterol diet or wild type hypercholesterolemic mice treated with NGnitro-L-arginine methyl ester (L-NAME), a NOS inhibitor
Our results showed that a single injection of adenoviral COMP-Ang[1] gene or two successive injections of COMPAng[1] recombinant protein into the corpus cavernosum induced complete and long-lasting recovery of erectile function and blood flow in hypercholesterolemic mice, which was accompanied by enhanced cavernous angiogenesis, eNOS phosphorylation, and cGMP expression
Summary
Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable. We demonstrate that local delivery of the soluble, stable, and potent Ang[1] variant, COMP-Ang[1] gene or protein, into the penises of hypercholesterolemic mice increases cavernous angiogenesis, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function and cavernous blood flow up to 8 weeks after treatment. We determined the effectiveness of COMP-Ang[1] in promoting cavernous angiogenesis and restoring erectile function in a mouse model of hypercholesterolemic ED induced by a high-cholesterol diet. Our results showed that a single injection of adenoviral COMP-Ang[1] gene (ad-COMP-Ang1) or two successive injections of COMPAng[1] recombinant protein into the corpus cavernosum induced complete and long-lasting recovery of erectile function and blood flow in hypercholesterolemic mice, which was accompanied by enhanced cavernous angiogenesis, eNOS phosphorylation, and cGMP expression. COMP-Ang[1] involved in the maintenance of integrity of endothelial cell-cell junction (EC junction) by down-regulating expression of histone deacelylase 2 (HDAC2) in the penis of hypercholesterolemic mice and in primary cultured mouse cavernous endothelial cells (MCECs) in vitro
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
