Vascular Smooth Muscle Cell Singnal Transduction in Vascular Remodeling

血管紧张素II（Angiotensin II，Ang II）是肾素-血管紧张素系统的主要肽类激素，除了在血压和循环容量的调节中起关键作用外，还在多种心血管疾病的发生发展中发挥重要作用。虽然血管紧张素II是一种有效的肥大，迁移和抗凋亡的VSMC在细胞培养系统中的因子，负责促生长，细胞迁移和存活促进行动的分子机制尚未完全理解的血管紧张素II。我们已经报道了血管紧张素Ⅱ诱导VSMC多种细胞内蛋白酪氨酸磷酸化，激活ras原癌基因产物（Ras）和丝裂原活化蛋白（MAP）激酶，以及c-fos的表达，在本研究中，我们揭示了酪氨酸激酶（s）和磷脂酰肌醇3-激酶的活性是血管紧张素Ⅱ诱导Ras激活所必需的，而这两者都不是Ang II刺激的MAP激酶激活的先决条件。腺病毒介导的Ha-Ras显性失活突变体的表达完全抑制ANG 11诱导的Ras激活，但未能抑制MAP激酶激活和这种血管收缩剂对蛋白质合成的刺激。因此，血管紧张素II刺激MAP激酶和蛋白质合成的Ras的非依赖性途径在VSMC。p130 <Cas>^ -c-Crk II<Cas>复合物可能在血管紧张素II的作用中起作用，此外，Akt/蛋白激酶B（PKB），一种具有pleckstrin同源结构域的丝氨酸/苏氨酸激酶，也被证明在血管紧张素II处理后被激活。由于Akt/PKB在生长因子诱导的抗细胞凋亡作用中起重要作用，提示Akt/PKB在Ang Ⅱ的抗细胞凋亡作用中起重要作用。

Angiotensin II (Ang II), the main peptide hormone of the renin-angiotensin system, has been known to play an important role in the development of various cardiovascular diseases in addition to its key regulatory role in the regulation of blood pressure and circulating volume. Although Ang II is a potent hypertrophic, migratory and anti-apoptotic factor of VSMC in a cell culture system, molecular mechanisms responsible for growth promoting, cell migrating and survival promoting actions of Ang II have not been fully understood. We have reported that Ang II induces tyrosine phosphorylation of multiple intracellular proteins, activation of the ras protooncogene product (Ras) and mitogen-activated protein (MAP) kinases and expression of c-fos in VSMC.In the present research, we revealed that activities of tyrosine kinase(s) and phosphatidylinositol 3-kinase are required for Ang II-induced Ras activation, whereas neither of them is not prerequisite for Ang II-stimulated MAP kinase activation. Adenovirus-mediated expression of a dominant negative mutant of Ha-Ras completely inhibited ANG 11-induced Ras activation, but failed to inhibit MAP kinase activation and stimulation of protein synthesis by this vasoconstrictor. Thus, Ang II stimulates MAP kinases and protein synthesis by a Ras-independent pathway in VSMC.Further, we showed that Ang II stimulates tyrosine phosphorylation and association of two adapter proteins, . p130^<Cas> and c-Crk II, proposing that p130^<Cas> -c-Crk II complex could play a role in Ang II action in VSMC.Moreover, Akt/protein kinase B (PKB), a serine/threonine kinase with a pleckstrin homology domain, is also shown to be activated in response to Ang II treatment. Since Akt/PKB is known to play an important role in growth factor-induced anti-apoptotic effect, these results suggested a role of Akt/PKB in anti-apoptotic effect of Ang II.Thus, Ang II activates multiple signaling pathways, resulting pleiotropic effects of Mg 11 on VS MC.