Vascular Smooth Muscle Cell Singnal Transduction in Vascular Remodeling

血管紧张素II （Ang II）是肾素-血管紧张素系统的主要肽激素，除了在调节血压和循环容量方面发挥关键调节作用外，还在各种心血管疾病的发生中发挥重要作用。虽然在细胞培养系统中，Ang II是一种有效的VSMC增生性、迁移性和抗凋亡因子，但其促进生长、细胞迁移和促进生存的分子机制尚不完全清楚。我们已经报道了Ang II诱导多种细胞内蛋白的酪氨酸磷酸化，ras原癌基因产物（ras）和丝裂原活化蛋白（MAP）激酶的激活以及VSMC中c-fos的表达。在本研究中，我们发现酪氨酸激酶(s)和磷脂酰肌醇3-激酶的活性是Ang ii诱导的Ras激活所必需的，而它们都不是Ang ii刺激的MAP激酶激活的先决条件。腺病毒介导的Ha-Ras显性阴性突变体的表达完全抑制ANG - 11诱导的Ras激活，但未能抑制MAP激酶的激活和这种血管收缩剂对蛋白质合成的刺激。因此，在VSMC中，Ang II通过ras不依赖的途径刺激MAP激酶和蛋白质合成。此外，我们发现Ang II刺激酪氨酸磷酸化和两种连接蛋白的结合。p130^<Cas> -c-Crk II复合物可能在VSMC中发挥Ang II的作用。此外，Akt/protein kinase B (PKB)，一种丝氨酸/苏氨酸激酶，具有pleckstrin同源结构域，也被证明在Ang II处理下被激活。由于Akt/PKB在生长因子诱导的抗凋亡作用中发挥重要作用，这些结果提示Akt/PKB在Ang II的抗凋亡作用中发挥作用。因此，Ang II激活了多种信号通路，从而导致Mg 11对VS MC的多效性作用。

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.