Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor
Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor
复制标题
DOI：
10.1096/fj.02-0939com
复制
发表时间：
2003-09-01
期刊：
影响因子：
4.8
通讯作者：
Elenius, K
中科院分区：
文献类型：
--
作者：
Iivanainen, E;Nelimarkka, L;Elenius, K
血管内皮细胞（EC）对血管平滑肌细胞（SMC）的募集对于血管生成是必不可少的。内皮衍生的肝素结合EGF样生长因子（HB-EGF）显示通过SMC中的ErbB 1和ErbB 2受体的信号传导介导该过程。1)ErbB配体的分析表明，原代EC仅表达HB-EGF和神经调节蛋白-1。2)原代SMCs表达ErbB 1和ErbB 2，但不表达ErbB 3和ErbB 4。3)与其已知的受体特异性一致，重组HBEGF，而不是neuregulin-1，刺激ErbB 1和ErbB 2的酪氨酸磷酸化和SMCs的迁移。4)中和HB-EGF或抑制ErbB 1或ErbB 2阻断了70 - 90%的EC刺激SMC迁移的潜力。此外，5）血管生成素-1（一种EC效应器，在体内将SMC样细胞募集到血管结构中发挥作用）通过涉及内皮HB-EGF上调的机制增强EC刺激的SMC迁移。最后，6）对发育中的人体组织的免疫组织化学分析表明，HB-EGF在体内在与SMC或周细胞相关的EC中表达，但在与SMC无关的玻璃体血管的EC中不表达。这些结果表明HB-EGF和ErbB受体在EC募集SMC中起重要作用，并阐述了血管生成素发挥其血管效应的机制。
Recruitment of vascular smooth muscle cells (SMC) by endothelial cells (EC) is essential for angiogenesis. Endothelial-derived heparin binding EGF-like growth factor (HB- EGF) was shown to mediate this process by signaling via ErbB1 and ErbB2 receptors in SMCs. 1) Analysis of ErbB-ligands demonstrated that primary ECs expressed only HB- EGF and neuregulin-1. 2) Primary SMCs expressed ErbB1 and ErbB2, but not ErbB3 or ErbB4. 3) Consistent with their known receptor specificities, recombinant HBEGF, but not neuregulin-1, stimulated tyrosine phosphorylation of ErbB1 and ErbB2 and migration in SMCs. 4) Neutralization of HB- EGF or inhibition of ErbB1 or ErbB2 blocked 70 - 90% of the potential of ECs to stimulate SMC migration. Moreover, 5) angiopoietin-1, an EC effector with a role in recruitment of SMC-like cells to vascular structures in vivo, enhanced EC-stimulated SMC migration by a mechanism involving up-regulation of endothelial HB- EGF. Finally, 6) immunohistochemical analysis of developing human tissues demonstrated that HB- EGF was expressed in vivo in ECs associated with SMCs or pericytes but not in ECs of the hyaloid vessels not associated with SMCs. These results suggest an important role for HB- EGF and ErbB receptors in the recruitment of SMCs by ECs and elaborate on the mechanism by which angiopoietins exert their vascular effects.