Complex interactions between the laminin alpha 4 subunit and integrins regulate endothelial cell behavior in vitro and angiogenesis in vivo.
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.
Gonzalez
Annette M
AM
Department of Cell and Molecular Biology, The Feinberg School of Medicine at Northwestern University, Chicago, IL 60611, USA.
Gonzales
Meredith
M
Herron
G Scott
GS
Nagavarapu
Usha
U
Hopkinson
Susan B
SB
Tsuruta
Daisuke
D
Jones
Jonathan C R
JC
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000473:pathology; D002448:Cell Adhesion; D002478:Cells, Cultured; D019281:Dimerization; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D039201:Integrin alpha3beta1 / Q000502:physiology*; D039121:Integrin alpha6beta1 / Q000502:physiology*; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D007680:Kidney Neoplasms / Q000473:pathology; D007797:Laminin / Q000502:physiology*; D008024:Ligands; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D039201:Integrin alpha3beta1; D039121:Integrin alpha6beta1; D039302:Integrin alphaVbeta3; C501369:LAMA4 protein, human; C501370:Lama4 protein, mouse; D007797:Laminin; D008024:Ligands; D021122:Protein Subunits