Reiss Yvonne, Droste Jasmin, Heil Matthias, Tribulova Silvia, Schmidt Mirko HH, Schaper Wolfgang, Dumont Daniel J, Plate Karl H
Institute of Neurology, Frankfurt University Medical School, 60528 Frankfurt, Germany.
Circ Res. 2007 Jul 6;101(1):88-96. doi: 10.1161/CIRCRESAHA.106.143594. Epub 2007 May 31.
Angiopoietins play important roles in the formation of neovessels and complex vascular networks. Angiopoietin (Ang)-1 and Ang-2 belong to a family of growth factors that display opposing effects on the activation of Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2). Endothelial Ang-2 expression is associated with vessel destabilization and regulates a balance between vascular regression and growth. To elucidate, in particular, the role of Ang-2 after arterial artery occlusion in the mouse limb, we applied a transgenic animal model with targeted Ang-2 expression in endothelial cells. We show here that restoration of blood flow in Ang-2:Tie1 transgenic mice is dramatically impaired when Ang-2 expression is induced in the vasculature. The defective restoration of perfusion in Ang-2 transgenic mice is evidenced by reduced collateral artery growth, which typically occurs to compensate for flow deficits after occlusion of the large conductance artery. Furthermore, reduced movement capacities and higher incidents of necrosis are consequently observed in the transgenic limbs as compared with controls. Mechanistically, the observed effects are attributed to defective smooth muscle cell recruitment in Ang-2 transgenic mice. Moreover, distinct Ang-2 levels in the genetically modified animals clearly correlated with the magnitude of reduced perfusion. In conclusion, our studies define Ang-2 as an important molecule for the progression of collateral artery growth and angiogenesis during ischemia and suggest precise Ang-2 dosage activities to accomplish blood vessel growth.
血管生成素在新血管和复杂血管网络的形成中发挥重要作用。血管生成素（Ang）-1和Ang-2属于一类生长因子家族，它们对Tie2（具有免疫球蛋白和表皮生长因子同源结构域2的酪氨酸激酶）的激活具有相反的作用。内皮细胞Ang-2的表达与血管不稳定相关，并调节血管消退和生长之间的平衡。为了特别阐明小鼠肢体动脉闭塞后Ang-2的作用，我们应用了一种在内皮细胞中靶向表达Ang-2的转基因动物模型。我们在此表明，当在脉管系统中诱导Ang-2表达时，Ang-2:Tie1转基因小鼠的血流恢复显著受损。Ang-2转基因小鼠灌注恢复缺陷表现为侧支动脉生长减少，侧支动脉生长通常发生在大传导动脉闭塞后以补偿血流不足。此外，与对照组相比，转基因肢体的运动能力降低且坏死发生率更高。从机制上讲，观察到的效应归因于Ang-2转基因小鼠中平滑肌细胞募集缺陷。此外，转基因动物中不同的Ang-2水平与灌注减少的程度明显相关。总之，我们的研究将Ang-2定义为缺血期间侧支动脉生长和血管生成进程中的重要分子，并表明精确的Ang-2剂量活性对于实现血管生长至关重要。
