ED 21. Cavernous angiogenesis as a novel therapeutic strategy for erectile dysfunction

Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable. Recently, a link between ED and cardiovascular disease was uncovered and both diseases were shown to share the same vascular risk factors with endothelial cell dysfunction being the common denominator between these two conditions. Neovascularization, therefore, has emerged as a novel concept for curing ED by reestablishing structural and functional microvasculature.

There have been researches targeting angiogenesis in the corpus cavernosum to develop local therapy for ED with vascular causes. Vascular endothelial growth factor (VEGF) is believed to stimulate formation of new blood vessels in response to ischemia and other pathologic states through mechanisms involving eNOS. Thus, direct intracavernous injection of VEGF gene/protein was tried in a variety of diseases model, including casatration, traumatized iliac arteries, hyperlipidemia, or venoocclusive dysfunction and resulted in better, but not complete erectile function.

A strategy to enhance angiopoietin-1/Tie2 signal pathway was primarily considered for penile angiogenesis based on our findings that cavernous angiopoietin-1 and their downstream signal molecules are downregulated in ED with hypercholesterolemia. We found that combined local delivery of both angiopoietin-1 and VEGF genes in hypercholesterolemic rats significantly increases cavernous endothelial contents, which results in complete recovery of erectile function, compared with those in the group treated with either therapy alone. We had successive projects to evaluate the effect of cartilage oligomeric matrix protein (COMP) - a variant of agniopoietin-1 and much more potent than that, in the treatment of ED.

Local delivery of the soluble COMP-ang1 into the penises of hypercholesterolemic mice was found to increase penile angiogenesis with increased endothelial contents, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function and cavernous blood flow up to 8 weeks after the treatment. COMP-Ang1-induced promotion of penile angiogenesis and erectile function was eNOS-dependent. Moreover, treatment of COMP-Ang1 completely restored endothelial cell-to-cell junction proteins, including vascular endothelial-cadherin, zonula occludens-1, occludin and claudin-5 and decreased cavernous endothelial permeability, which is regulated by HDAC2 in the cavernous endothelium. In either STZ-induced diabetic mice or db/db mice, intrapenile treatment of COMP-Ang1 protein also increased cavernous angiogenesis with cavernous endothelial proliferation and restoration of endothelial cell-to-cell junction, which in turn resulted in restoration of erectile function up to 4 weeks after the treatment. Moreover, endothelial protective effects, such as marked decreases in the expression of p47phox and iNOS, in the generation of superoxide anion and nitrotyrosine, and in the number of apoptotic cells in the corpus cavernosum tissue, were noted in COMP-Ang1-treated diabetic mice.

A series of our studies show that enhancement of angiopoietin-1/Tie2 signaling promotes endothelial cell regeneration and strengthens the endothelial cell integrity. We expect that local therapy with recombinant Ang1 protein will be a novel, curative treatment modality for vascular disease-induced erectile dysfunction.