Hungarian Academy of Sciences and Semmelweis University, Research Group for Pediatrics and Nephrology, Institute of Pathophysiology, Semmelweis University, Faculty of Medicine, Budapest Hungary.
Am J Physiol Cell Physiol. 2012 Jan 1;302(1):C267-76. doi: 10.1152/ajpcell.00138.2011. Epub 2011 Oct 19.
Angiotensin II (ANG II), the major effector molecule of the renin-angiotensin system (RAS), is a powerful vasoactive mediator associated with hypertension and renal failure. In this study the permeability changes and its morphological attributes in endothelial cells of human umbilical vein (HUVECs) were studied considering the potential regulatory role of ANG II. The effects of ANG II were compared with those of vascular endothelial growth factor (VEGF). Permeability was determined by 40 kDa FITC-Dextran and electrical impedance measurements. Plasmalemmal vesicle-1 (PV-1) mRNA levels were measured by PCR. Endothelial cell surface was studied by atomic force microscopy (AFM), and caveolae were visualized by transmission electron microscopy (TEM) in HUVEC monolayers. ANG II (10(-7) M), similarly to VEGF (100 ng/ml), increased the endothelial permeability parallel with an increase in the number of cell surface openings and caveolae. AT1 and VEGF-R2 receptor blockers (candesartan and ZM-323881, respectively) blunted these effects. ANG II and VEGF increased the expression of PV-1, which could be blocked by candesartan or ZM-323881 pretreatments and by the p38 mitogem-activated protein (MAP) kinase inhibitor SB-203580. Additionally, SB-203580 blocked the increase in endothelial permeability and the number of surface openings and caveolae. In conclusion, we have demonstrated that ANG II plays a role in regulation of permeability and formation of cell surface openings through AT1 receptor and PV-1 protein synthesis in a p38 MAP kinase-dependent manner in endothelial cells. The surface openings that increase in parallel with permeability may represent transcellular channels, caveolae, or both. These morphological and permeability changes may be involved in (patho-) physiological effects of ANG II.
血管紧张素 II（ANG II）是肾素-血管紧张素系统（RAS）的主要效应分子，是一种与高血压和肾衰竭相关的强大血管活性介质。在这项研究中，考虑到 ANG II 的潜在调节作用，研究了其对人脐静脉内皮细胞（HUVEC）通透性变化及其形态特征的影响。将 ANG II 的作用与血管内皮生长因子（VEGF）的作用进行了比较。通过 40 kDa FITC-Dextran 和电阻抗测量来确定通透性。通过 PCR 测量质膜小泡-1（PV-1）mRNA 水平。在 HUVEC 单层中，通过原子力显微镜（AFM）研究内皮细胞表面，通过透射电子显微镜（TEM）观察 caveolae。ANG II（10(-7) M），与 VEGF（100ng/ml）相似，增加了内皮细胞通透性，同时增加了细胞表面开口和 caveolae 的数量。AT1 和 VEGF-R2 受体阻滞剂（坎地沙坦和 ZM-323881）分别）减弱了这些作用。ANG II 和 VEGF 增加了 PV-1 的表达，坎地沙坦或 ZM-323881 预处理和 p38 丝裂原激活蛋白（MAP）激酶抑制剂 SB-203580 可以阻断这种作用。此外，SB-203580 阻断了内皮细胞通透性和表面开口及 caveolae 数量的增加。总之，我们已经证明，ANG II 通过 AT1 受体和 p38 MAP 激酶依赖性方式在内皮细胞中通过 PV-1 蛋白合成在调节通透性和细胞表面开口形成中发挥作用。通透性平行增加的表面开口可能代表跨细胞通道、caveolae 或两者兼有。这些形态和通透性变化可能与 ANG II 的（病理）生理作用有关。
