Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment
Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment
复制标题
DOI：
10.1182/blood-2005-09-012807
复制
发表时间：
2006-08-15
期刊：
影响因子：
20.3
通讯作者：
Lin, Pengnian Charles
中科院分区：
文献类型：
--
作者：
Kobayashi, Hanako;DeBusk, Laura M.;Lin, Pengnian Charles
内皮细胞 (EC) 和壁细胞之间的通讯对于血管成熟至关重要。遗传学研究表明，血管生成素/Tie2 信号传导可能在血管成熟过程中周细胞或平滑肌细胞 (SMC) 的募集中发挥作用。然而，其分子机制尚不清楚。我们使用微阵列技术分析了内皮细胞 (EC) 中受血管生成素-1 (Ang1)（Tie2 的激动剂配体）调节的基因。我们观察到，壁细胞运动的介质肝细胞生长因子（HGF）被 AngII 刺激上调。我们通过培养血管内皮细胞的 Northern 印迹和 Western 印迹分析证实了这一发现。此外，在共培养测定中，用AngII刺激EC增加了SMC向内皮细胞的迁移。添加中和性抗HGF抗体抑制Angl诱导的SMC募集，表明Angl诱导SMC迁移是由HGF的增加引起的。有趣的是，Tie2 的拮抗配体 Ang2 抑制 Ang1 诱导的 HGF 产生和 Ang1 诱导的 SMC 迁移。最后，我们发现转基因小鼠中 Tie2 的缺失减少了 HGF 的产生。总的来说，我们的数据揭示了 Ang/Tie2 信号传导在调节血管成熟中的一种新机制，并表明 Ang1 和 Ang2 之间的微妙平衡在此过程中至关重要。
Communication between endothelial cells (ECs) and mural cells is critical in vascular maturation. Genetic studies suggest that angiopoietin/Tie2 signaling may play a role in the recruitment of pericytes or smooth muscle cells (SMCs) during vascular maturation. However, the molecular mechanism is unclear. We used microarray technology to analyze genes regulated by angiopoietin-1 (Ang1), an agonist ligand for Tie2, in endothelial cells (ECs). We observed that hepatocyte growth factor (HGF), a mediator of mural cell motility, was up-regulated by Angll stimulation. We confirmed this finding by Northern blot and Western blot analyses in cultured vascular endothelial cells. Furthermore, stimulation of ECs with Angll increased SMC migration toward enclothelial cells in a coculture assay. Addition of a neutralizing anti-HGF antibody inhibited Angl-induced SMC recruitment, indicating that the induction of SMC migration by Angll was caused by the increase of HGF. Interestingly, Ang2, an antagonist ligand of Tie2, inhibited Angl-induced HGF production and Angl-induced SMC migration. Finally, we showed that deletion of Tie2 in transgenic mouse reduced HGF production. Collectively, our data reveal a novel mechanism of Ang/Tie2 signaling in regulating vascular maturation and suggest that a delicate balance between Angl and Ang2 is critical in this process.