Endothelial alpha5 and alphav integrins cooperate in remodeling of the vasculature during development.
Integrin cell adhesion receptors and fibronectin, one of their extracellular matrix ligands, have been demonstrated to be important for angiogenesis using functional perturbation studies and complete knockout mouse models. Here, we report on the roles of the alpha5 and alphav integrins, which are the major endothelial fibronectin receptors, in developmental angiogenesis. We generated an integrin alpha5-floxed mouse line and ablated alpha5 integrin in endothelial cells. Unexpectedly, endothelial-specific knockout of integrin alpha5 has no obvious effect on developmental angiogenesis. We provide evidence for genetic interaction between mutations in integrin alpha5 and alphav and for overlapping functions and compensation between these integrins and perhaps others. Nonetheless, in embryos lacking both alpha5 and alphav integrins in their endothelial cells, initial vasculogenesis and angiogenesis proceed normally, at least up to E11.5, including the formation of apparently normal embryonic vasculature and development of the branchial arches. However, in the absence of endothelial alpha5 and alphav integrins, but not of either alone, there are extensive defects in remodeling of the great vessels and heart resulting in death at ~E14.5. We also found that fibronectin assembly is somewhat affected in integrin alpha5 knockout endothelial cells and markedly reduced in integrin alpha5/alphav double-knockout endothelial cell lines. Therefore, neither alpha5 nor alphav integrins are required in endothelial cells for initial vasculogenesis and angiogenesis, although they are required for remodeling of the heart and great vessels. These integrins on other cells, and/or other integrins on endothelial cells, might contribute to fibronectin assembly and vascular development.
van der Flier
Arjan
A
Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Badu-Nkansah
Kwabena
K
Whittaker
Charles A
CA
Crowley
Denise
D
Bronson
Roderick T
RT
Lacy-Hulbert
Adam
A
Hynes
Richard O
RO
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D002460:Cell Line; D004727:Endothelium / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism / Q000502:physiology; D039482:Integrin alpha5 / Q000378:metabolism* / Q000502:physiology*; D039564:Integrin alphaV / Q000378:metabolism* / Q000502:physiology*; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III; D017469:Receptors, Fibronectin / Q000378:metabolism / Q000502:physiology
D005353:Fibronectins; D039482:Integrin alpha5; D039564:Integrin alphaV; D016023:Integrins; D017469:Receptors, Fibronectin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III