TGF-β Signaling in Endothelial Cells, but Not Neuroepithelial Cells, Is Essential for Cerebral Vascular Development

Lab Invest. 2011 Nov;91(11):1554-63. doi: 10.1038/labinvest.2011.124. Epub 2011 Aug 29.

Abstract

The various organs of the body harbor blood vessel networks that display unique structural and functional features; however, the mechanisms that control organ-specific vascular development and physiology remain mostly unknown. In the developing mouse brain, αvβ8 integrin-mediated TGF-β activation and signaling is essential for normal blood vessel growth and sprouting. Whether integrins activate TGF-β signaling pathways in vascular endothelial cells (ECs), neural cells, or both, has yet to be determined. Here, we have generated and characterized mice in which TGF-β receptors are specifically deleted in neuroepithelial cells via Nestin-Cre, or in ECs via a novel Cre transgenic strain (Alk1(GFPCre)) in which Cre is expressed under control of the endogenous activin receptor-like kinase 1 (Alk1) promoter. We report that deletion of Tgfbr2 in the neuroepithelium does not impact brain vascular development. In contrast, selective deletion of the Tgfbr2 or Alk5 genes in ECs result in embryonic lethality because of brain-specific vascular pathologies, including blood vessel morphogenesis and intracerebral hemorrhage. These data reveal for the first time that αvβ8 integrin-activated TGF-βs regulate angiogenesis in the developing brain via paracrine signaling to ECs.

Publication types

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

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type II
  • Animals
  • Astrocytes / metabolism
  • Cerebrum / blood supply*
  • Cerebrum / embryology*
  • Endothelial Cells / physiology*
  • Galactosides
  • Immunohistochemistry
  • Indoles
  • Integrases
  • Intermediate Filament Proteins
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic / physiology*
  • Nerve Tissue Proteins
  • Nestin
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Vitronectin / metabolism
  • Signal Transduction / physiology*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Galactosides
  • Indoles
  • Intermediate Filament Proteins
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Receptors, Transforming Growth Factor beta
  • Receptors, Vitronectin
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse
  • Receptor, Transforming Growth Factor-beta Type II
  • Cre recombinase
  • Integrases
  • 5-bromo-4-chloro-3-indolyl beta-galactoside