ANGIOTENSIN SIGNALING AND VASCULAR GROWTH

血管紧张素II(AII)是心血管内稳态的关键调节因子 控制血管张力、内分泌和细胞生长。它的 这些作用是通过AII受体AT1的特定亚型来实现的 和2点。这两种受体都是与细胞内偶联的七种跨膜受体 通过异源三聚体G蛋白的信号通路。AT2受体是 在胎儿组织中高表达，但在胎儿组织中分布有限 成体，暗示在组织生长和分化中起作用。 所有对细胞生长和DNA合成的作用都已得到充分证实 在培养的大鼠血管平滑肌细胞中。在这项提案中，我们希望 探讨MAP依赖的信号通路在急性淋巴细胞白血病中的作用 增长效应。我们将确定AII使用的受体亚型 以及MAP激酶和相关蛋白的激活的幅度和动力学 AII在这些细胞中的蛋白激酶，并将决定所需 在AII的生长效应中MAP激酶的激活。利用DNA介导的基因 转移，我们还将确定MAP激酶的机制 被所有人激活。AII是一种有效的MAP激酶转录激活剂 磷酸酶(MKP)。MKPs选择性地调节MAP激酶和 应激激活蛋白激酶。我们将确定是否所有人 MKP的诱导决定了AII信号的特异性。 我们还将在一个发展调节的模型中审查所有II的行动 VSMC成长，养猪。ALL不能诱导成年猪的DNA合成 VSMC，但确实刺激新生儿VSMC的生长。我们将决定 这些发育差异在AII的发育效应中是否 胎儿心血管系统。

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.