ANGIOTENSIN SIGNALING AND VASCULAR GROWTH

血管紧张素II（AII）是心血管稳态的关键调节因子 控制血管张力、内分泌和细胞生长。 其 作用通过AII受体的特定亚型AT1介导 在AT2 两者都是七个跨膜受体， 通过异源三聚体G蛋白的信号通路。 AT2受体是 在胎儿组织中高度表达，但在 成体，表明在组织生长和分化中的作用。 所有对细胞生长和DNA合成的作用都已得到证实 在培养的大鼠血管平滑肌细胞中。 在这一建议中，我们希望 研究MAP激酶依赖性信号通路在AII中的作用， 增长效应。 我们将确定AII利用的受体亚型， 以及MAP激酶活化的幅度和动力学以及相关的 蛋白激酶的AII在这些细胞，并将决定需要 MAP激酶激活对AII生长的影响。 利用DNA介导的基因 转移，我们还将确定MAP激酶是通过什么机制， 被所有人激活。 AII是MAP激酶的有效转录激活剂 磷酸酶（MKPs）。 MKPs选择性地调节MAP激酶， 应激激活蛋白激酶。 我们将决定是否所有的 MKP的诱导决定了AII信号传导的特异性。 我们还将在一个发展调节模型中研究AII的行为， 血管平滑肌细胞生长，猪。 所有这些都不能诱导成年猪的DNA合成 但刺激新生儿VSMCs的生长。 我们将确定 是否这些发展差异在AII的发展影响， 胎儿的心血管系统

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.