Kou Baijun, Vatish Manu, Singer Donald R J
Clinical Pharmacology, Clinical Science Research Institute, Warwick Medical School, University of Warwick Coventry, CV2 2DX, UK.
Vascul Pharmacol. 2007 Oct;47(4):199-208. doi: 10.1016/j.vph.2007.06.011. Epub 2007 Aug 11.
Reduced capillary density (rarefaction) is an early event of cardiovascular disease. The PI-3K-Akt pathway is a key player in anti-endothelial cells (ECs) apoptosis. VEGF is a key growth factor for angiogenesis. We investigated the effect of Angiotensin II (Ang II) on ECs survival signalling and angiogenesis in vitro. We found that Ang II had a biphasic effect on Akt phosphorylation by western blotting analysis. Low concentration Ang II caused a dose-dependent increase in Akt phosphorylation, while high concentration of Ang II led to a decrease of Akt phosphorylation. This effect was negative regulated by its type II receptor. Ang II 10(-4) M induced ECs apoptosis by its type II receptor was completely blocked by VEGF. Cell viability was increased by Ang II 10(-6) M and decreased by Ang II 10(-4) M. It was further decreased by pre-treatment with PI-3K/Akt inhibitor LY294002, but unaffected by p38-MAPK inhibitor SB202190. Ang II 10(-4) M reduced ECs' proliferation and vascular tube length, which were in part regulated by type II receptor. Our findings support a dose-dependent role of Ang II in effect on ECs survival and angiogenesis by PI-3K/Akt pathway. The anti-angiogenic effect of Ang II was mediated by its type II receptor.
毛细血管密度降低（稀疏化）是心血管疾病的早期事件。PI-3K-Akt信号通路是抗内皮细胞（ECs）凋亡的关键参与者。血管内皮生长因子（VEGF）是血管生成的关键生长因子。我们研究了血管紧张素II（Ang II）对体外培养的内皮细胞存活信号和血管生成的影响。通过蛋白质免疫印迹分析，我们发现Ang II对Akt磷酸化具有双相作用。低浓度的Ang II导致Akt磷酸化呈剂量依赖性增加，而高浓度的Ang II则导致Akt磷酸化减少。这种作用受到其II型受体的负调控。Ang II 10(-4) M通过其II型受体诱导内皮细胞凋亡，而VEGF可完全阻断该作用。Ang II 10(-6) M可提高细胞活力，而Ang II 10(-4) M则降低细胞活力。用PI-3K/Akt抑制剂LY294002预处理可进一步降低细胞活力，但p38丝裂原活化蛋白激酶（p38-MAPK）抑制剂SB202190对其无影响。Ang II 10(-4) M可降低内皮细胞的增殖和血管管长度，这部分受II型受体调控。我们的研究结果支持Ang II通过PI-3K/Akt信号通路对内皮细胞存活和血管生成具有剂量依赖性作用。Ang II的抗血管生成作用是由其II型受体介导的。
