Calvi Cristina, Dentelli Patrizia, Pagano Marco, Rosso Arturo, Pegoraro Marco, Giunti Sara, Garbarino Giovanni, Camussi Giovanni, Pegoraro Luigi, Brizzi Maria Felice
Department of Internal Medicine, University of Torino, Torino, Italy.
Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):511-8. doi: 10.1161/01.ATV.0000116864.86607.35. Epub 2004 Jan 15.
To characterize the molecules and the mechanisms regulating the neoangiogenetic process in advanced atherosclerotic plaques.
Western blot and immunofluorescence analysis of atherosclerotic specimens demonstrated that unlike neovessels from early lesions that expressed vascular endothelial growth factor (VEGF) and angiopoietin1 (Angio1), vessels from advanced lesions expressed VEGF and angiopoietin 2 (Angio2). Moreover, only few neovessels from advanced lesions showed a positive immunostaining for proliferating cell nuclear antigen. Angio1-elicited and Angio2-elicited intracellular events in endothelial cells (EC) demonstrated that while Angio1 triggered Erk1/Erk2 mitogen activated protein kinases (MAPK) and Akt activation, Angio2 (50 ng/mL) induced STAT5 activation and p21waf expression and increased the fraction of cells in G1. Both Angio2-mediated events were abrogated by expressing a dominant negative STAT5 construct (DeltaSTAT5). Consistent with the expression of Angio2 in neovessels of advanced lesions a transcriptionally active STAT5 was detected. Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions.
In advanced lesions, the activation of the Tie2-mediated STAT5 signaling pathway may negatively regulate vessel growth.
描述晚期动脉粥样硬化斑块中调节新生血管生成过程的分子和机制。
对动脉粥样硬化标本进行蛋白质免疫印迹和免疫荧光分析表明，与早期病变中的新生血管表达血管内皮生长因子（VEGF）和血管生成素1（Angio1）不同，晚期病变中的血管表达VEGF和血管生成素2（Angio2）。此外，晚期病变中只有少数新生血管对增殖细胞核抗原呈阳性免疫染色。内皮细胞（EC）中血管生成素1和血管生成素2引发的细胞内事件表明，血管生成素1触发细胞外信号调节激酶1/细胞外信号调节激酶2（Erk1/Erk2）丝裂原活化蛋白激酶（MAPK）和Akt激活，而血管生成素2（50 ng/mL）诱导信号转导和转录激活因子5（STAT5）激活和p21waf表达，并增加G1期细胞比例。通过表达显性负性STAT5构建体（DeltaSTAT5）可消除血管生成素2介导的这两个事件。与血管生成素2在晚期病变新生血管中的表达一致，检测到转录活性STAT5。此外，免疫共沉淀实验显示在晚期而非早期病变的新生内膜血管中存在STAT5/Tie2分子复合物。
在晚期病变中，Tie2介导的STAT5信号通路的激活可能对血管生长起负调节作用。
