HoxB5 induces endothelial sprouting in vitro and modifies intussusceptive angiogenesis in vivo involving angiopoietin-2
HoxB5 induces endothelial sprouting in vitro and modifies intussusceptive angiogenesis in vivo involving angiopoietin-2
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DOI：
10.1093/cvr/cvp133
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发表时间：
2009-08-01
影响因子：
10.8
通讯作者：
Moser, Martin
中科院分区：
文献类型：
--
作者：
Winnik, Stephan;Klinkert, Mei;Moser, Martin
同源盒（Hox）蛋白是脊椎动物和无脊椎动物胚胎模式、细胞分化、增殖和迁移的转录调节因子。越来越多的证据表明Hox蛋白参与内皮细胞调节。我们之前已经表明，HoxB5上调血管内皮生长因子受体-2，从而促进内皮前体细胞分化。本文旨在阐明HoxB5在血管生成中的作用。采用人脐静脉内皮细胞球形实验研究了内皮细胞的发芽。我们研究了鸡（Gallus Gallus）绒毛膜尿囊膜的体内血管生成。通过定量PCR分析促血管生成因子的表达谱。血管生成素-2 （Ang2）启动子及其缺失片段克隆到pGL3报告系统中进行转录活性分析。我们在体外观察到HoxB5促进内皮细胞发芽和调节粘附分子的表达。因此，我们在体内观察到HoxB5对血管生长的修饰。HoxB5的作用让人想起血管生成素的作用。我们证明了Ang2在HoxB5过表达时被上调，而HoxB5的作用被血管生成素拮抗剂可溶性Tie-2所消除。HoxB5对Ang2具有激活作用，Ang2对内皮细胞发芽和血管协调生长至关重要。
Homeobox (Hox) proteins are transcriptional regulators in embryonic patterning, cell differentiation, proliferation, and migration in vertebrates and invertebrates. A growing body of evidence suggests that Hox proteins are involved in endothelial cell regulation. We have shown earlier that HoxB5 upregulates vascular endothelial growth factor receptor-2 and thereby contributes to enhanced endothelial precursor cell differentiation. Here we aim to elucidate the role of HoxB5 in angiogenesis.Endothelial cell sprouting was investigated in the human umbilical vein endothelial cell spheroid assay. We investigated in vivo angiogenesis in the chick (Gallus gallus) chorioallantoic membrane assay. Expression profiling of proangiogenic factors was done by quantitative PCR. The angiopoietin-2 (Ang2) promoter and deletion fragments thereof were cloned into the pGL3 reporter system for analysis of transcriptional activity. We observed that HoxB5 enhances endothelial cell sprouting and modulates the expression of adhesion molecules in vitro. Accordingly, we observed a modification of vascular growth by HoxB5 in vivo. The HoxB5 effect is reminiscent of the effects of angiopoietins. We demonstrate that Ang2 is upregulated upon HoxB5 overexpression and that the HoxB5 effect is abolished by the angiopoietin antagonist soluble Tie-2.HoxB5 has an activating effect on Ang2 that is essential for endothelial cell sprouting and coordinated vascular growth.