Chen Jian-Xiong, Chen Ying, DeBusk Laura, Lin Wenyu, Lin Pengnain Charles
Department of Radiation Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave., Preston Research Bldg., Rm. 315, Nashville, TN 37232, USA.
Am J Physiol Heart Circ Physiol. 2004 Jul;287(1):H187-95. doi: 10.1152/ajpheart.01058.2003.
Inflammation and angiogenesis are associated with pathological disorders. TNF-alpha is a major inflammatory cytokine that also regulates angiogenesis. TNF-alpha has been shown to regulate Tie-2 and angiopoietin (Ang) expression, but the functional significance is less clear. In this study, we showed that TNF-alpha induced a weak angiogenic response in a mouse cornea assay. Systemic overexpression of Ang-1 or Ang-2 dramatically increased corneal angiogenesis induced by TNF-alpha. In the absence of TNF-alpha, neither Ang-1 nor Ang-2 promoted corneal angiogenesis. Low doses (0-25 ng/ml) of TNF-alpha increased vascular branch formation of cultured endothelial cells. Overexpression of Ang-1 or Ang-2 enhanced the effects of TNF-alpha. These data suggest that Tie-2 signaling synergistically amplifies and participates in TNF-alpha-mediated angiogenesis. In addition, high doses (>/=50 ng/ml) of TNF-alpha induced apoptosis in endothelial cells, but addition of Ang-1 or Ang-2 significantly reduced cell death. Enhanced endothelial cell survival was correlated with Akt phosphorylation. Collectively, our data reveal dual functional roles of Tie-2: low doses enhance TNF-alpha-induced angiogenesis, and high doses attenuate TNF-alpha-induced cell death. The study provides evidence supporting a role for Tie-2 in inflammatory angiogenesis.
炎症和血管生成与病理紊乱相关。肿瘤坏死因子-α（TNF-α）是一种主要的炎症细胞因子，也调节血管生成。已表明TNF-α调节Tie-2和血管生成素（Ang）的表达，但其功能意义尚不清楚。在本研究中，我们发现在小鼠角膜试验中TNF-α诱导了微弱的血管生成反应。Ang-1或Ang-2的全身过表达显著增加了TNF-α诱导的角膜血管生成。在没有TNF-α的情况下，Ang-1和Ang-2均未促进角膜血管生成。低剂量（0-25 ng/ml）的TNF-α增加了培养的内皮细胞的血管分支形成。Ang-1或Ang-2的过表达增强了TNF-α的作用。这些数据表明Tie-2信号协同放大并参与TNF-α介导的血管生成。此外，高剂量（≥50 ng/ml）的TNF-α诱导内皮细胞凋亡，但添加Ang-1或Ang-2可显著减少细胞死亡。内皮细胞存活的增强与Akt磷酸化相关。总体而言，我们的数据揭示了Tie-2的双重功能作用：低剂量增强TNF-α诱导的血管生成，高剂量减弱TNF-α诱导的细胞死亡。该研究提供了支持Tie-2在炎症性血管生成中作用的证据。
