Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease

J Clin Invest. 2012 Jul;122(7):2454-68. doi: 10.1172/JCI60842. Epub 2012 Jun 1.

Abstract

In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lymphocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Cytokines / metabolism
  • DNA-Binding Proteins
  • Demyelinating Diseases
  • Gene Expression Regulation
  • Humans
  • Inflammation / metabolism
  • Interleukin-1beta / physiology
  • Lymphocytes / pathology
  • Lysosome-Associated Membrane Glycoproteins
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Multiple Sclerosis / metabolism*
  • Multiple Sclerosis / pathology
  • Nerve Tissue Proteins / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Nuclear Proteins / metabolism
  • Occludin
  • Permeability
  • Primary Cell Culture
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor A / physiology*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Cln5 protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Interleukin-1beta
  • Lysosome-Associated Membrane Glycoproteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • NeuN protein, mouse
  • Nuclear Proteins
  • OCLN protein, human
  • Occludin
  • Ocln protein, mouse
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2