Endothelial 5 and v integrins cooperate in remodeling of the vasculature during development

Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Development (Impact Factor: 6.46). 07/2010; 137(14):2439-49. DOI: 10.1242/dev.049551
Source: PubMed


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.

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    • "In vivo, FN1-binding integrin heterodimers containing α4 or α3 chains do not appear to cooperate with integrin α5β1 during early embryogenesis (Yang et al., 1999). αv-containing integrins cooperate with integrin α5β1 in early mouse embryogenesis to facilitate gastrulation as well as in midgestation, during remodeling of the pharyngeal arch arteries (Yang et al., 1999; van der Flier et al., 2010). In zebrafish, αv-containing integrins were shown to be important for the establishment of the left–right asymmetry by regulating morphogenesis of the Kupffer's vesicle. "
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