ANGIOTENSIN SIGNALING AND VASCULAR GROWTH

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Angiotensin II (AII) is a key regulator of cardiovascular homeostasis controlling vascular tone, endocrine secretion and cellular growth. Its actions are mediated through specific subtypes of the AII receptor, AT1 and AT2. Both are seven transmembrane receptors coupled to intracellular signaling pathways through heterotrimeric G proteins. The AT2 receptor is highly expressed in fetal tissues but shows a restricted distribution in the adult, suggesting a role in tissue growth and differentiation. AII action on cellular growth and DNA synthesis have been well established in cultured rat vascular smooth muscle cells. In this proposal, we wish to examine the role of MAP kinase-dependent signaling pathways in AII's growth effects. We will determine the receptor subtypes utilized by AII and the magnitude and kinetics of activation of MAP kinases and related protein kinases by AII in these cells and will determine the requirement of MAP kinase activation in AII's growth effects. Using DNA-mediated gene transfer, we will also determine the mechanism by which MAP kinase is activated by AII. AII is a potent transcriptional activator of MAP kinase phosphatases (MKPs). MKPs selectively regulate both MAP kinases and stress-activated protein kinases. We will determine whether AII's induction of MKPs dictates the specificity of AII signaling. We will also examine AII's actions in a developmentally regulated model of VSMC growth, the pig. All does not induce DNA synthesis in adult porcine VSMCs but does stimulate growth in neonatal VSMCs. We will determine whether these developmental differences in AII's developmental effects in the fetal cardiovascular system.