Complex interactions between the laminin α4 subunit and integrins regulate endothelial cell behavior in vitro and angiogenesis in vivo

Annette M. Gonzalez, Meredith Gonzales, G. Scott Herron, Usha Nagavarapu, Susan B. Hopkinson, Daisuke Tsuruta, Jonathan C.R. Jones*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

The α4 laminin subunit is a component of the basement membrane of blood vessels where it codistributes with the integrins αvβ3, α3β1, and α6β1. An antibody against the G domain (residues 919-1207; G919-1207) of the α4 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 G919-1207 to support endothelial cell adhesion. In particular, endothelial cell adhesion to G919-1207 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 αvβ3 and β1 and a combination of antibodies against β3 and α6 integrin subunits inhibit endothelial cell attachment to G919-1207. Moreover, both αvβ3 and α3β1 integrin bind with high affinity to G919-1207. Together, our studies demonstrate that the G domain of laminin α4 chain is a specific, high affinity ligand for the αvβ3 and α3β1 integrin heterodimers and that these integrins, together with α6β1, function cooperatively to mediate endothelial cell-α4 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 αvβ3 integrin in angiogenesis.

Original languageEnglish (US)
Pages (from-to)16075-16080
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number25
DOIs
StatePublished - Dec 10 2002

Keywords

  • Blood vessels
  • Matrix
  • Matrix receotor

ASJC Scopus subject areas

  • General

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