VEGFA acts downstream of SHH in the adult penis, since SHH treatment induces PTCH1 and VEGFA and SHH inhibition downregulates these targets. SHH induction of VEGFA is supported by reports in the literature in cardiac tissue and in ischemic limb. Schwann cells have been shown to induce VEGF expression. Mutations that eliminate Schwann cells prevent proper arteriogenesis, and in mutant embryos containing disorganized nerves the trajectory of blood vessel branching is altered to follow the nerve. These data suggest that peripheral nerves provide a template that determines the organotypic pattern of blood vessel branching and arterial differentiation during development, via local secretion of VEGFA.
The localization of SHH in Schwann cells of the penis and the ability of SHH to induce VEGFA expression in the penis suggest that a similar mechanism may be active in adult penile nerves and vasculature. Thus SHH may represent a nexus between neural and vascular control of penile morphology.
These studies show that SHH inhibition causes apoptosis in the corpora cavernosa, that morphology changes caused by SHH inhibition in the rat penis are reversible, that CN injury causes a significant decrease in the active form of SHH protein in the corpora cavernosa, and that SHH treatment at the time of CN injury significantly decreases post-CN injury-induced apoptosis. Thus, SHH stabilizes alterations of the corpora cavernosal smooth muscle following CN injury and has significant potential to be developed into a therapy to prevent postprostatectomy apoptosis while the cavernous nerve regenerates.