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

Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2102-7. doi: 10.1161/01.ATV.0000144813.44650.75. Epub 2004 Sep 9.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / blood*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Neuropathies / blood*
  • Diabetic Neuropathies / metabolism
  • Disease Models, Animal
  • Fibroblasts / cytology
  • Hedgehog Proteins
  • Humans
  • Laser-Doppler Flowmetry / methods
  • Male
  • Neovascularization, Physiologic / drug effects*
  • Neural Conduction / drug effects
  • Neural Conduction / physiology
  • Perfusion / methods
  • Plant Lectins / analysis
  • Plant Lectins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Regional Blood Flow / drug effects
  • Regional Blood Flow / physiology
  • Sciatic Nerve / blood supply
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / physiology
  • Streptozocin
  • Trans-Activators / pharmacology*
  • Vasa Nervorum / chemistry
  • Vasa Nervorum / drug effects*
  • Vasa Nervorum / growth & development*
  • Vasa Nervorum / pathology
  • Vascular Endothelial Growth Factor A / pharmacology


  • Griffonia simplicifolia lectins
  • Hedgehog Proteins
  • Plant Lectins
  • SHH protein, human
  • Trans-Activators
  • Vascular Endothelial Growth Factor A
  • Streptozocin