Hu Changping, Dandapat Abhijit, Mehta Jawahar L
Department of Internal Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205-7199, USA.
Hypertension. 2007 Nov;50(5):952-7. doi: 10.1161/HYPERTENSIONAHA.107.096446. Epub 2007 Sep 24.
Angiotensin II (Ang II) induces angiogenesis by stimulating reactive oxygen species-dependent vascular endothelial growth factor (VEGF) expression. Ang II via type 1 receptor upregulates the expression of LOX-1, a lectin-like receptor for oxidized low-density lipoprotein. LOX-1 activation, in turn, upregulates Ang II type 1 receptor expression. We postulated that interruption of the feedback loop between Ang II and LOX-1 might attenuate Ang II-induced VEGF expression and capillary formation. In vitro experiments showed that Ang II (1 nmol/L) induced the expression of LOX-1 and VEGF and enhanced capillary formation from human coronary endothelial cells in Matrigel assay. Ang II-mediated expression of LOX-1 and VEGF, capillary formation, intracellular reactive oxygen species generation, and phosphorylation of p38 as well as p44/42 mitogen-activated protein kinases, were suppressed by anti-LOX-1 antibody, nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin and the Ang II type 1 receptor blocker losartan, but not by the Ang II type 2 receptor blocker PD123319. Expression of VEGF and capillary formation induced by Ang II were also inhibited by the p44/42 mitogen-activated protein kinase inhibitor U0126 and the p38 mitogen-activated protein kinase inhibitor SB203580. In ex vivo experiments, Ang II stimulated capillary sprouting from aortic rings from wild-type mice, and this phenomenon was significantly attenuated by pretreatment of aortic rings with anti-LOX-1 antibody, apocynin, and losartan, but not by PD123319. Importantly, Ang II-induced capillary sprouting was minimal from aortic rings from LOX-1 null mice compared with wild-type mice. These findings suggest that small concentrations of Ang II promote capillary formation by inducing the expression of VEGF via Ang II type 1 receptor/LOX-1-mediated stimulation of the reactive oxygen species-mitogen-activated protein kinase pathway.
血管紧张素 II（Ang II）通过刺激活性氧依赖性血管内皮生长因子（VEGF）表达来诱导血管生成。Ang II 通过 1 型受体上调 LOX-1 的表达，LOX-1 是一种针对氧化型低密度脂蛋白的凝集素样受体。反过来，LOX-1 的激活会上调 Ang II 1 型受体的表达。我们推测，Ang II 与 LOX-1 之间反馈环的中断可能会减弱 Ang II 诱导的 VEGF 表达和毛细血管形成。体外实验表明，Ang II（1 nmol/L）可诱导 LOX-1 和 VEGF 的表达，并在基质胶试验中增强人冠状动脉内皮细胞的毛细血管形成。抗 LOX-1 抗体、烟酰胺腺嘌呤二核苷酸磷酸氧化酶抑制剂夹竹桃麻素和 Ang II 1 型受体阻滞剂氯沙坦可抑制 Ang II 介导的 LOX-1 和 VEGF 表达、毛细血管形成、细胞内活性氧生成以及 p38 以及 p44/42 丝裂原活化蛋白激酶的磷酸化，但 Ang II 2 型受体阻滞剂 PD123319 则无此作用。Ang II 诱导的 VEGF 表达和毛细血管形成也受到 p44/42 丝裂原活化蛋白激酶抑制剂 U0126 和 p38 丝裂原活化蛋白激酶抑制剂 SB203580 的抑制。在离体实验中，Ang II 刺激野生型小鼠主动脉环的毛细血管芽生，而用抗 LOX-1 抗体、夹竹桃麻素和氯沙坦预处理主动脉环可显著减弱这种现象，但 PD123319 则无此作用。重要的是，与野生型小鼠相比，来自 LOX-1 基因敲除小鼠主动脉环的 Ang II 诱导的毛细血管芽生极少。这些发现表明，低浓度的 Ang II 通过 Ang II 1 型受体/LOX-1 介导的活性氧-丝裂原活化蛋白激酶途径刺激 VEGF 表达，从而促进毛细血管形成。
