Integrin Beta8 is essential for vascular development in the mouse. Integrin Beta8 -/- embryos fail to survive gestation and develop vascular defects in the yolk sac and intracerebral hemorrhage. The similarity of this phenotype to that of TGF-Beta1/TGF-BetaRs-deficient mice, along with recent biochemical studies, suggests that one function of integrin Beta8 is to activate TGF-Beta 1 signaling during development. The experiments presented in this proposal are designed to further characterize the vascular defects observed in integrin Beta8-deficient mice using histology, immunohistochemistry, and electron microscopy. Integrin Beta8 expression will be determined in wildtype embryos by in situ hybridization and immunohistochemistry. Determining the relationship between integrin Beta8 expression and cellular defects in integrin Beta8 -/- embryos would be valuable to understand how integrin Beta8 functions. Furthermore, immunohistochemistry and genetic approaches will be used to examine the TGF-Beta1 signaling pathway to evaluate the possibility that reduced TGF-Beta1 activity may account for the vascular defects in mutant embryos. In addition, expression of known angiogenic factors in the mutant will be analyzed to test the involvement of dysregalated signal(s). The proposed studies will help to elucidate the mechanisms by which vascular development is regulated and the function of integrin Beta8 in this process. Through this work, we hope to understand the molecular mechanisms involved in vascular development and maturation which will be invaluable in understanding pathogenesis of human vascular diseases and in developing therapeutic treatments.
