ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway

Dev Cell. 2012 Mar 13;22(3):489-500. doi: 10.1016/j.devcel.2012.02.005.

Abstract

Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-β/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors
  • Activin Receptors, Type I / physiology*
  • Activin Receptors, Type II
  • Animals
  • Arteriovenous Malformations / enzymology*
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • Cell Cycle Proteins / physiology
  • Dipeptides / pharmacology
  • Disease Models, Animal
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors / physiology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology*
  • Receptors, Notch / physiology*
  • Repressor Proteins / physiology
  • Retina / growth & development
  • Retina / pathology
  • Signal Transduction
  • Smad Proteins / physiology
  • Telangiectasia, Hereditary Hemorrhagic / drug therapy
  • Telangiectasia, Hereditary Hemorrhagic / physiopathology
  • Vascular Endothelial Growth Factors / physiology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Dipeptides
  • GDF2 protein, human
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors
  • Hey1 protein, mouse
  • Hey2 protein, mouse
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Receptors, Notch
  • Repressor Proteins
  • Smad Proteins
  • Vascular Endothelial Growth Factors
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse