Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents

J Clin Invest. 2011 Aug;121(8):3005-23. doi: 10.1172/JCI46358. Epub 2011 Jul 11.

Abstract

Stroke is the leading cause of long-term disability and the third leading cause of death in the United States. While most research thus far has focused on acute stroke treatment and neuroprotection, the exploitation of endogenous brain self-repair mechanisms may also yield therapeutic strategies. Here, we describe a distinct type of stroke treatment, the naturally occurring extracellular matrix fragment of perlecan, domain V, which we found had neuroprotective properties and enhanced post-stroke angiogenesis, a key component of brain repair, in rodent models of stroke. In both rat and mouse models, Western blot analysis revealed elevated levels of perlecan domain V. When systemically administered 24 hours after stroke, domain V was well tolerated, reached infarct and peri-infarct brain vasculature, and restored stroke-affected motor function to baseline pre-stroke levels in these multiple stroke models in both mice and rats. Post-stroke domain V administration increased VEGF levels via a mechanism involving brain endothelial cell α5β1 integrin, and the subsequent neuroprotective and angiogenic actions of domain V were in turn mediated via VEGFR. These results suggest that perlecan domain V represents a promising approach for stroke treatment.

Publication types

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

MeSH terms

  • Animals
  • Brain / pathology
  • Extracellular Matrix / metabolism
  • Heparan Sulfate Proteoglycans / chemistry*
  • Humans
  • Integrin alpha5beta1
  • Ischemia / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Neovascularization, Pathologic*
  • Neuroprotective Agents / pharmacology*
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Stroke / drug therapy
  • Stroke / physiopathology*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Heparan Sulfate Proteoglycans
  • Integrin alpha5beta1
  • Neuroprotective Agents
  • Vascular Endothelial Growth Factor A
  • perlecan