Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy

Objective - The embryonic morphogen sonic hedgehog (SHh) has been shown to induce neovascularization of ischemic tissue but has not been shown to play a role in regulating vascular nerve supply. Accordingly, we investigated the hypothesis that systemic injection of SHh protein could improve nerve blood flow and function in diabetic neuropathy (DN). Methods and Results - Twelve weeks after induction of diabetes with streptozotocin, motor and sensory nerve conduction velocities (MCV and SCV) of the sciatic nerves were significantly reduced in diabetic rats. SHh-treated diabetic rats demonstrated marked improvement of both MCV and SCV ( P < 0.05). Laser Doppler perfusion imaging showed that nerve blood flow was significantly reduced in the diabetic rats but was restored in SHh-treated diabetic rats ( P < 0.05 versus diabetic saline-treated rats) to levels similar to those achieved with vascular endothelial growth factor-2 (VEGF-2) gene therapy. In vivo perfusion of Bandeuraea simplicifolia (BS)-1 lectin showed marked reduction in the vasa nervora in diabetic sciatic nerves but restoration of nerve vasculature to nondiabetic levels in the SHh-treated and plasmid DNA encoding human VEGF-2 (phVEGF-2)- treated diabetic nerves. Interestingly, the SHh-induced vasculature was characterized by larger diameter and more smooth muscle cell-containing vessels, compared with VEGF-2 gene-treated diabetic rats. Conclusions - These data indicate that Shh induces arteriogenesis and restores nerve function in DN.