Inhibition of endogenous VEGF impedes revascularization and astroglial proliferation: roles for VEGF in brain repair

Exp Neurol. 2003 Jun;181(2):241-57. doi: 10.1016/s0014-4886(03)00039-6.

Abstract

Vascular endothelial growth factor (VEGF) is upregulated following injury to the CNS. Our previous work has shown that exogenous application of VEGF promotes angiogenesis, blood-brain barrier permeability, and astroglial mitogenicity in the traumatized brain. To develop a model that could link endogenously secreted VEGF to brain tissue repair, a specific neutralizing antibody to VEGF was infused by osmotic minipump directly into the neocortex and striatum for up to 1 week. Tissues adjacent to the infusion/wound site were analyzed for specific vascular and astroglial protein markers and proliferation, necrosis/apoptosis (via TUNEL staining), VEGF, the VEGF receptors flt-1 and flk-1, and bFGF expression using immunohistochemistry and semi-quantitative RT-PCR. Neutralization of native VEGF caused significant decreases in angiogenic activity, astroglial proliferation, and nestin immunoexpression, while vascular and astroglial degeneration was substantially increased, resulting in much larger wound cavities when compared to controls. The hindrance of brain tissue repair occurred despite an increase in bFGF expression at the wound sites. VEGF appears to be an integral factor in CNS wound healing that is essential for vascular endothelial proliferation and survival and may also be necessary for astroglial proliferation and maintenance during the repair of brain injury.

Publication types

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

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Astrocytes / cytology*
  • Astrocytes / drug effects
  • Cell Division / drug effects
  • Cell Division / physiology
  • Corpus Striatum / cytology*
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology*
  • Endothelial Growth Factors / antagonists & inhibitors*
  • Endothelial Growth Factors / physiology
  • Fibroblast Growth Factor 2 / biosynthesis
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Intercellular Signaling Peptides and Proteins / physiology
  • Intermediate Filament Proteins / biosynthesis
  • Lymphokines / antagonists & inhibitors*
  • Lymphokines / physiology
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology*
  • Nerve Tissue Proteins*
  • Nestin
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Vascular Endothelial Growth Factor / biosynthesis
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Antibodies
  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Intermediate Filament Proteins
  • Lymphokines
  • Nerve Tissue Proteins
  • Nes protein, rat
  • Nestin
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2
  • Receptors, Vascular Endothelial Growth Factor