Development of the cardiovascular system is under complex control and is highly susceptible to genetic perturbations. Recent studies have identified a network of transcription factors that play critical roles in regulating cardiovascular development. Far less is known, however, about how extracellular matrix signaling controls cell behavior in this context. The essential role of CCN1 (CYR61), a matricellular angiogenic protein, in cardiovascular development has been recently established. Ccn1-null mice suffer embryonic death due to impaired vessel bifurcation, vessel integrity, and atrioventricular valvuoseptal morphogenesis. Although Ccn1 mice are largely viable, 20% of them exhibit atrial septal defects similar to those found in some patients with human congenital heart disease. The expression of Ccn1 and its close homologue Ccn2 (CTGF) is overlapping throughout cardiovascular development, and tightly associated with vascular diseases and myocardial infarction. However, Ccn2-null mice show skeletal rather than cardiovascular phenotypes, suggesting that Ccn1 and Ccn2 may serve overlapping functions. Mechanistically, CCN proteins bind directly to distinct integrins, which have been shown to mediate various CCN activities in cell culture systems. However, the role of integrins in CCN proteins function in vivo is unknown. This proposal seeks to test the hypothesis that underlying the diverse functions of CCN proteins are their ability to regulate angiogenesis, the synthesis or assembly of the extracellular matrix, and cell survival or cell death in a context dependent manner. These notions will be tested in three specific aims. First, the role of CCN1 in maintaining vascular structure will be determined, and the contribution of CCN1-a? integrin interaction in cardiovascular development will be assessed. Second, the possible overlapping functions of Ccn1 and Ccn2 will be dissected in double or compound mutants. Finally, the apoptotic activities of CCN proteins in cultured cardiomyocytes will be investigated, as will the role of CCN1 in cardiomyocyte apoptosis after myocardial infarction. Together, these studies will provide novel insights into how CCN proteins regulate cardiovascular development through extracellular matrix signaling, and shed light on their roles in cardiovascular diseases. ? ? ?
