Saito Momomi, Hamasaki Maho, Shibuya Masabumi
Division of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Cancer Sci. 2003 Sep;94(9):782-90. doi: 10.1111/j.1349-7006.2003.tb01519.x.
The angiopoietin-1 (Ang1)/Tie2 receptor system is known to be important for angiogenesis and vascular remodeling. However, its contribution to the survival and morphogenesis of endothelial cells is still not well elucidated. In this study, we analyzed the role of the Ang1/Tie2 pathway in cell survival and tube formation using a human umbilical vein endothelial (HUVE) cell and fibroblast co-culture system. In this system, which mimics angiogenesis in vivo, fibroblasts secrete a basal level of vascular endothelial growth factor (VEGF), and Ang1 stimulated tube formation. However, anti-VEGF or anti-VEGF receptor-2 neutralizing antibody blocked the Ang1-induced tube formation. Furthermore, other angiogenic factors such as hepatic growth factor (HGF) and basic fibroblast growth factor (bFGF) showed the same phenotype as Ang1, i.e., a stimulatory effect only in the presence of endogenous VEGF. The Ang1-promoted tube formation was mainly due to suppression of HUVE cell apoptosis in a PI3-kinase-dependent manner. These findings suggest that Ang1 stimulates tube formation in vivo via the PI3-kinase/Akt pathway, but this effect takes place only in a VEGF-dependent manner.
血管生成素-1（Ang1）/Tie2受体系统已知对血管生成和血管重塑很重要。然而，其对内皮细胞存活和形态发生的作用仍未得到充分阐明。在本研究中，我们使用人脐静脉内皮（HUVE）细胞与成纤维细胞共培养系统分析了Ang1/Tie2通路在细胞存活和管形成中的作用。在这个模拟体内血管生成的系统中，成纤维细胞分泌基础水平的血管内皮生长因子（VEGF），并且Ang1刺激管形成。然而，抗VEGF或抗VEGF受体-2中和抗体阻断了Ang1诱导的管形成。此外，其他血管生成因子如肝细胞生长因子（HGF）和碱性成纤维细胞生长因子（bFGF）表现出与Ang1相同的表型，即仅在内源性VEGF存在时具有刺激作用。Ang1促进的管形成主要是由于以PI3激酶依赖性方式抑制HUVE细胞凋亡。这些发现表明，Ang1通过PI3激酶/Akt通路在体内刺激管形成，但这种作用仅以VEGF依赖性方式发生。
