In the adult, protease-activated receptors (PARs) respond to coagulation proteases to help orchestrate cellular responses involved in hemostasis, inflammation and repair. In the previous project period, we showed that PARs also play distinct and important roles in embryonic development. Indeed, PAR1 signaling in endothelial cells is required for proper remodeling and/or integrity of developing blood vessels in mouse embryos. What biochemical and physiological processes does PAR1 monitor during blood vessel formation? Which endothelial cell responses to PAR1 activation are important for proper vessel development? We hypothesize that the coagulation cascade and PARs together provide a system for monitoring and regulating the formation, remodeling, and integrity of developing blood vessels. Toward testing this hypothesis we shall first determine whether PARs sense coagulation proteases during mouse embryonic development, and whether activation of PARs account for the roles of coagulation factors in this context. Specific questions include a) Does combined deficiency of PARs phenocopy tissue factor deficiency? b) Is tissue factor expression in or around blood vessels necessary and sufficient to support embryonic development? and c) Can embryos bearing prothrombin mutations be rescued by complementary mutations in PAR1? We shall next determine which signaling pathways are important for the function of PAR1 and other GPCRs in endothelial cells during vascular development by ablating the function of specific G protein pathways in endothelial cells in the mouse embryo. We expect these studies to illuminate a novel role for the coagulation cascade and PARs and to provide new insights regarding the mechanisms governing vascular development and perhaps new blood vessel formation in other settings.
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