Complex interactions between the laminin alpha4 subunit and integrins regulate endothelial cell behavior in vitro and angiogenesis in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-12, Vol.99 (25), p.16075
• Main Authors: Gonzalez, Annette M, Gonzales, Meredith, Herron, G Scott, Nagavarapu, Usha
• Format: Article
• Language: English
• Subjects: Blood vessels; Cellular biology
• ISSN: 0027-8424; 1091-6490

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; G919-1207) 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 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 alphavbeta3 and beta1 and a combination of antibodies against alpha3 and alpha6 integrin subunits inhibit endothelial cell attachment to G919-1207. Moreover, both alphavbeta3 and alpha3beta1 integrin bind with high affinity to G919-1207. 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.