Sustained delivery of VEGF maintains innervation and promotes reperfusion in ischemic skeletal muscles via NGF/GDNF signaling

Mol Ther. 2014 Jul;22(7):1243-1253. doi: 10.1038/mt.2014.76. Epub 2014 Apr 28.

Abstract

Tissue reinnervation following trauma, disease, or transplantation often presents a significant challenge. Here, we show that the delivery of vascular endothelial growth factor (VEGF) from alginate hydrogels ameliorates loss of skeletal muscle innervation after ischemic injury by promoting both maintenance and regrowth of damaged axons in mice. Nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) mediated VEGF-induced axonal regeneration, and the expression of both is induced by VEGF presentation. Using both in vitro and in vivo modeling approaches, we demonstrate that the activity of NGF and GDNF regulates VEGF-driven angiogenesis, controlling endothelial cell sprouting and blood vessel maturation. Altogether, these studies produce evidence of new mechanisms of VEGF action, further broaden the understanding of the roles of NGF and GDNF in angiogenesis and axonal regeneration, and suggest approaches to improve axonal and ischemic tissue repair therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Mice
  • Muscle, Skeletal / innervation*
  • Nerve Growth Factor / metabolism*
  • Nerve Regeneration / genetics
  • Nerve Regeneration / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Vascular Endothelial Growth Factor A / administration & dosage*
  • Vascular Endothelial Growth Factor A / therapeutic use*
  • Wound Healing

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Vascular Endothelial Growth Factor A
  • Nerve Growth Factor