Choi Jin-Hwa, Nguyen Minh-Phuong, Lee Dongjin, Oh Goo-Taeg, Lee You-Mie
National Basic Research Laboratory of Vascular Homeostasis Regulation, Kyungpook National University, Daegu 702-701, Korea ; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 702-701, Korea.
Mol Cells. 2014 Jun;37(6):487-96. doi: 10.14348/molcells.2014.0119. Epub 2014 Jun 18.
Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout (AGT(+/-)) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of AGT(+/-) EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in AGT(+/-) EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-1α and -2α were downregulated in AGT(+/-) early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-1α were suppressed in AGT(+/-) EPCs. In AGT(+/-) mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis.
血管紧张素原（AGT）是血管紧张素I的前体，已知其参与肿瘤血管生成并与冠状动脉粥样硬化的发病机制相关。本研究旨在确定AGT在内皮祖细胞（EPCs）的肿瘤进展和转移中所起的作用。研究发现，AGT杂合敲除（AGT(+/-)）细胞形成的EPC集落数量少于野生型（WT）细胞，且AGT(+/-) EPCs的迁移和管形成能力显著低于WT EPCs。此外，血管内皮生长因子（VEGF）、Flk1、血管生成素（Ang）-1、Ang-2、Tie-2、基质衍生因子（SDF）-1、C-X-C趋化因子受体4型（CXCR4）以及内皮型一氧化氮合酶（eNOS）在AGT(+/-) EPCs中的基因表达受到抑制。此外，在低氧条件下，AGT(+/-)早期EPCs中缺氧诱导因子（HIF）-1α和-2α的表达下调，提示对缺氧的反应减弱。而且，VEGF、上皮生长因子（EGF）或SDF-1α诱导的Akt/eNOS信号通路的激活在AGT(+/-) EPCs中受到抑制。在AGT(+/-)小鼠中，EPCs整合到肿瘤脉管系统的数量显著减少，肺肿瘤生长和黑色素瘤转移也减弱。总之，AGT是缺氧诱导的血管生成所必需的。
