Hoffmann Brian R, Stodola Timothy J, Wagner Jordan R, Didier Daniela N, Exner Eric C, Lombard Julian H, Greene Andrew S
From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee.
Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):433-445. doi: 10.1161/ATVBAHA.116.307787. Epub 2017 Jan 12.
Angiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1. Angiotensin 1 to 7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, whereas the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7).
This study shows that low-dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similar to a low, subpressor dose of AngII acting through AngII receptor type 1. In addition, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Using proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho family of GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen-activated protein kinase, and extracellular signal-related kinase signaling. Further experimental antagonism of extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinase signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7).
These results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII compared with the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AngII receptor type 1 signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of mitogen-activated protein kinase/extracellular signal-related kinase signaling in maintaining vascular function.
血管紧张素II（AngII）已被证明可调节血管生成，在高病理生理剂量下通过1型血管紧张素II受体引起血管收缩。通过Mas1受体起作用的血管紧张素1-7（Ang-(1-7)）可通过诱导血管舒张，对高病理生理水平的AngII起拮抗作用，而Ang-(1-7)信号传导对血管生成的影响尚不明确。更复杂的是，越来越多的证据表明，低于降压剂量的AngII会产生与Ang-(1-7)相似的表型。
本研究表明，低剂量的Ang-(1-7)通过Mas1受体起作用，促进血管生成和血管舒张，类似于低剂量、低于降压剂量的AngII通过1型血管紧张素II受体起作用。此外，我们通过体外成管实验表明，Ang-(1-7)增强了大鼠微血管内皮细胞的血管生成反应。使用蛋白质组学和基因组分析，确定了Mas1受体信号传导的下游成分，包括Rho家族的GTP酶、磷脂酰肌醇3激酶、蛋白激酶D1、丝裂原活化蛋白激酶和细胞外信号相关激酶信号传导。当用等摩尔低剂量的AngII或Ang-(1-7)刺激时，对细胞外信号相关激酶1/2和p38丝裂原活化蛋白激酶信号传导的进一步实验性拮抗抑制了内皮细胞成管和血管舒张。
这些结果显著扩展了已知的Ang-(1-7)/Mas1受体信号通路，并证明了与AngII正常化和Ang-(1-7)给药的有益作用相比，AngII升高和降低的病理作用之间的重要区别。在低配体浓度下观察到的Ang-(1-7)/Mas1和AngII/1型血管紧张素II受体信号传导的趋同表明血管系统存在细微的调节。这些数据也强化了丝裂原活化蛋白激酶/细胞外信号相关激酶信号传导在维持血管功能中的重要性。
