Endothelial β1 integrins regulate sprouting and network formation during vascular development

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Abstract
β1 integrins are important regulators of vascular differentiation and development, as their endothelial-specific deletion results in embryonic lethality. In the present study, we investigated the molecular mechanisms underlying the prominent vascular abnormalities that occur in the absence of β1 integrins. Because of the early embryonic lethality of knockout mice, we studied endothelial cell and vessel development in β1-integrin-deficient murine embryonic stem cells to gain novel insights into the role of β1 integrins in vasculo-angiogenesis. We found that vessel development was strongly defective in the mutant embryoid bodies (EBs), as only primitive and short sprouts developed from clusters of vascular precursors in β1 integrin−/− EBs, whereas complex network formation of endothelial tubes was observed in wild-type EBs. The vascular defect was due to deficient β1 integrin expression in endothelial cells, as its endothelial-specific re-expression rescued the phenotype entirely. The mechanism responsible for defective vessel formation was found to be reduced endothelial cell maturation, migration and elongation. Moreover, the lower number of endothelial cells in β1 integrin−/− EBs was due to an increased apoptosis versus proliferation rate. The enhanced apoptosis and proliferation of β1 integrin−/− endothelial cells was related to the elevation of peNOS and pAKT signaling molecules, respectively. Our data demonstrate that endothelial β1 integrins are determinants of vessel formation and that this effect is mediated via different signaling pathways.

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