VE-Cadherin-mediated cell-cell interaction suppresses sprouting via signaling to MLC2 phosphorylation

Curr Biol. 2009 Apr 28;19(8):668-74. doi: 10.1016/j.cub.2009.02.057. Epub 2009 Apr 2.

Abstract

During new blood vessel formation, the cessation of angiogenic sprouting is necessary for the generation of functional vasculature. How sprouting is halted is not known, but it is contemporaneous with the development of stable intercellular junctions [1]. We report that VE-cadherin, which is responsible for endothelial adherens junction organization [2, 3], plays a crucial role in the cessation of sprouting. Abrogating VE-cadherin function in an organotypic angiogenesis assay and in zebrafish embryos stimulates sprouting. We show that VE-cadherin signals to Rho-kinase-dependent myosin light-chain 2 phosphorylation, leading to actomyosin contractility [4], which regulates the distribution of VE-cadherin at cell-cell junctions. VE-cadherin antagonizes VEGFR2 signaling, and consequently, inhibition of VE-cadherin, Rho-kinase, or actomyosin contractility leads to VEGF-driven, Rac1-dependent sprouting. These findings suggest a novel mechanism by which cell-cell adhesion suppresses Rac1-dependent migration and sprouting by increasing actomyosin contractility at cell junctions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cardiac Myosins / genetics
  • Cardiac Myosins / metabolism*
  • Cell Communication / physiology*
  • Cell Line
  • Endothelial Cells / cytology
  • Endothelial Cells / physiology
  • Gene Knockdown Techniques
  • Heterocyclic Compounds, 4 or More Rings / metabolism
  • Humans
  • Intercellular Junctions / metabolism
  • Myosin Light Chains / genetics
  • Myosin Light Chains / metabolism*
  • Myosins / metabolism
  • Neovascularization, Physiologic
  • Phosphorylation
  • Signal Transduction / physiology*
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Zebrafish / anatomy & histology*
  • Zebrafish / embryology*
  • Zebrafish / physiology
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism

Substances

  • Actins
  • Antigens, CD
  • Cadherins
  • Heterocyclic Compounds, 4 or More Rings
  • Myosin Light Chains
  • cadherin 5
  • myosin light chain 2
  • blebbistatin
  • Vascular Endothelial Growth Factor Receptor-2
  • rho-Associated Kinases
  • Cardiac Myosins
  • Myosins
  • rac1 GTP-Binding Protein