Flow-dependent regulation of angiopoietin-2
Flow-dependent regulation of angiopoietin-2
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DOI：
10.1002/jcp.21229
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发表时间：
2008-02-01
影响因子：
5.6
通讯作者：
Morawietz, Henning
中科院分区：
文献类型：
--
作者：
Goettsch, Winfried;Gryczka, Corina;Morawietz, Henning
在动脉和静脉中，内皮细胞通过流动的血液不断地暴露于高或低的剪切应力。血管生成素-2（Angiopoietin-2，Ang-2）是血管成熟和内皮细胞静止的重要调节因子。在这项研究中，血管紧张素-2的流量依赖性调节进行了分析，在体外和体内。在人内皮细胞中，低流量（1 dyne/cm（2））24 h可上调Ang-2 mRNA、蛋白表达和释放，而高流量（30 dyne/cm（2））可下调Ang-2 mRNA、蛋白表达和释放。增加内皮NO合成酶的表达和NO的形成并不影响低或高流量对Ang-2的调节。低流量和高流量增加VEGF-A表达。抑制VEGFR-2可阻止低流量引起的Ang-2上调，但不能阻止高流量引起的Ang-2下调。此外，VEGF对Ang-2的上调通过高流量的应用而减少。叉头盒0（FOXO）转录因子FOXO 1已显示调节内皮细胞中的Ang-2表达。FOXO 1结合活性被高流量降低。转录因子FOXO 1的核定位不受低流量的影响，但被高流量减少。在体内，Ang-2在静脉中的表达高于动脉。动脉结扎增加血管紧张素-2在远端动脉低流量区的表达。我们的研究结果支持VEGF依赖的低流量区Ang-2的诱导，和FOXO 1依赖的高流量区Ang-2的下调。这些数据表明，一个新的机制，流量依赖性调节血管的稳定性和分化。
Endothelial cells are constantly exposed to high or low shear stress in arteries and veins by the flowing blood. Angiopoietin-2 (Ang-2) is acting as a critical regulator of vessel maturation and endothelial cell quiescence. In this study, flow-dependent regulation of Ang-2 was analyzed in vitro and in vivo. Ang-2 mRNA, protein expression and release was upregulated by 24 h of low (1 dyne/cm(2)), but downregulated by high flow (30 dyne/cm(2)) in human endothelial cells. Increased endothelial NO synthase expression and NO formation was not affecting regulation of Ang-2 by low or high flow. Low and high flow increased VEGF-A expression. Inhibition of VEGFR-2 prevented upregulation of Ang-2 by low flow, but not downregulation of Ang-2 by high flow. Furthermore, upregulation of Ang-2 by VEGF was reduced by application of high flow. Forkhead box 0 (FOXO) transcription factor FOXO1 has been shown to regulate Ang-2 expression in endothelial cells. FOXO1 binding activity was reduced by high flow. Nuclear localization of transcription factor FOXO1 was not changed by low flow, but reduced by high flow. In vivo, Ang-2 was higher expressed in veins compared to arteries. Arterial ligation augmented Ang-2 expression in distal arterial low flow areas. Our results support a VEGF-dependent induction of Ang-2 in low flow areas, and FOXO1-dependent downregulation of Ang-2 in high flow areas. These data suggest a new mechanism of flow-dependent regulation of vessel stability and differentiation.