Heparin desulfation modulates VEGF release and angiogenesis in diabetic wounds

J Control Release. 2015 Dec 28;220(Pt A):79-88. doi: 10.1016/j.jconrel.2015.10.028. Epub 2015 Oct 22.

Abstract

While vascular endothelial growth factor (VEGF) has been shown to be one of the key players in wound healing by promoting angiogenesis current clinical applications of this growth factor to the wound environment are poorly controlled and not sustainable. Hydrogels made of sulfated glycosaminoglycans (GAG) allow for the sustained release of growth factors since GAGs engage in electrostatic complexation of biomolecules. In here, we explore a set of hydrogels formed of selectively desulfated heparin derivatives and star-shaped poly(ethylene glycol) with respect to VEGF binding and release and anticoagulant activity. As a proof of concept, supportive effects on migration and tube formation of human umbilical vein endothelial cells were studied in vitro and the promotion of wound healing was followed in genetically diabetic (db/db) mice. Our data demonstrate that the release of VEGF from the hydrogels is modulated in dependence on the GAG sulfation pattern. Hydrogels with low sulfate content (11% of initial heparin) were found to be superior in efficacy of VEGF administration, low anticoagulant activity and promotion of angiogenesis.

Keywords: Angiogenesis; Glycosaminoglycans; Growth factors; Heparin; Hydrogels; VEGF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Complications / drug therapy*
  • Diabetes Mellitus / physiopathology*
  • Glycosaminoglycans / chemistry
  • Heparin / chemistry*
  • Humans
  • Hydrogels / chemistry
  • Male
  • Mice
  • Neovascularization, Physiologic / drug effects*
  • Sulfates / chemistry
  • Vascular Endothelial Growth Factor A / administration & dosage*
  • Vascular Endothelial Growth Factor A / metabolism
  • Wound Healing / drug effects*

Substances

  • Glycosaminoglycans
  • Hydrogels
  • Sulfates
  • Vascular Endothelial Growth Factor A
  • Heparin