Complex interactions between the laminin alpha 4 subunit and integrins regulate endothelial cell behavior in vitro and angiogenesis in vivo

Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16075-80. doi: 10.1073/pnas.252649399. Epub 2002 Nov 26.

Abstract

The alpha4 laminin subunit is a component of the basement membrane of blood vessels where it codistributes with the integrins alphavbeta3, alpha3beta1, and alpha6beta1. An antibody against the G domain (residues 919-1207; G(919-1207)) of the alpha4 laminin subunit inhibits angiogenesis in a mouse-human chimeric model, indicating the functional importance of this domain. Additional support for the latter derives from the ability of recombinant G(919-1207) to support endothelial cell adhesion. In particular, endothelial cell adhesion to G(919-1207) is half-maximal at 1.4 nM, whereas residues 919-1018 and 1016-1207 of the G domain are poor cellular ligands. Function blocking antibodies against integrins alphavbeta3 and beta1 and a combination of antibodies against alpha3 and alpha6 integrin subunits inhibit endothelial cell attachment to G(919-1207). Moreover, both alphavbeta3 and alpha3beta1 integrin bind with high affinity to G(919-1207). Together, our studies demonstrate that the G domain of laminin alpha4 chain is a specific, high affinity ligand for the alphavbeta3 and alpha3beta1 integrin heterodimers and that these integrins, together with alpha6beta1, function cooperatively to mediate endothelial cell-alpha4 laminin interaction and hence blood vessel development. We propose a model based on these data that reconcile apparent discrepancies in the recent literature with regard to the role of the alphavbeta3 integrin in angiogenesis.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Carcinoma, Renal Cell / pathology
  • Cell Adhesion
  • Cells, Cultured
  • Dimerization
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / metabolism
  • Humans
  • Integrin alpha3beta1 / physiology*
  • Integrin alpha6beta1 / physiology*
  • Integrin alphaVbeta3 / physiology*
  • Kidney Neoplasms / pathology
  • Laminin / physiology*
  • Ligands
  • Neovascularization, Physiologic / physiology*
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Protein Subunits
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Integrin alpha3beta1
  • Integrin alpha6beta1
  • Integrin alphaVbeta3
  • LAMA4 protein, human
  • Lama4 protein, mouse
  • Laminin
  • Ligands
  • Protein Subunits