Integrin Cytoplasmic Domain-Associated Protein-1 Attenuates Sprouting Angiogenesis
Integrin Cytoplasmic Domain-Associated Protein-1 Attenuates Sprouting Angiogenesis
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DOI：
10.1161/circresaha.110.217257
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发表时间：
2010-09-03
影响因子：
20.1
通讯作者：
Fischer, Andreas
中科院分区：
文献类型：
--
作者：
Bruetsch, Rene;Liebler, Sven S.;Fischer, Andreas
理论基础：ICAP1（整合素细胞质结构域相关蛋白-1）是β -1整合素和脑海绵状畸形（CCM）蛋白CCM1的特异性细胞内结合蛋白。ICAP1将CCM1招募到细胞膜上，并通过改变其构象激活CCM1。由于CCM1在心血管发育中起着关键作用，我们假设其激活物ICAP1参与了血管分化。目的：本研究的目的是明确ICAP1在内皮细胞中的作用。方法与结果：在体外（3D发芽血管生成）和体内（ICAP1沉默的人内皮细胞异种移植）中，原代人内皮细胞中ICAP1的缺失会导致过多的血管生成分支和网络形成。ICAP1增加细胞活力和毛细血管芽的初始形成，但阻止血管的生长。ICAP1抑制Rho激酶活性和ERK（细胞外信号调节激酶）磷酸化，诱导细胞周期抑制剂p21和p27的表达，导致内皮细胞增殖减少。然而，ICAP1促进内皮细胞存活和AKT磷酸化。全球基因表达分析显示，ICAP1的作用是由DELTA-NOTCH信号的强烈激活介导的。激活NOTCH1或沉默NOTCH配体DLL4，可显着影响ICAP1的作用，并阻断NOTCH切割，可挽救内皮细胞中ICAP1介导的缺陷。ICAP1和NOTCH1均可降低ESM1（内皮细胞特异性分子-1）的表达，而ESM1的沉默会扰乱血管内皮生长因子-或成纤维细胞生长因子- 2诱导的新生血管生成。结论：在这项研究中，我们发现ICAP1是一种新的调节因子，可以防止过度的发芽血管生成。（Circ Res. 2010; 107: 592-601）
Rationale: The ICAP1 (integrin cytoplasmic domain-associated protein-1) is a specific intracellular binding protein of beta 1-integrins and the cerebral cavernous malformation (CCM) protein CCM1. ICAP1 recruits CCM1 to the cell membrane and activates CCM1 by changing its conformation. Because CCM1 plays a critical role for cardiovascular development, we hypothesized that its activator ICAP1 is involved in vascular differentiation.Objective: The objective of this study was to define the role of ICAP1 in endothelial cells.Methods and Results: Loss of ICAP1 in primary human endothelial cells causes excessive angiogenic branching and network formation in vitro (3D sprouting angiogenesis) and in vivo (xenotransplantation of ICAP1-silenced human endothelial cells). ICAP1 increases cell motility and the initial formation of capillary sprouts but prevents vessel outgrowth. ICAP1 inhibits Rho kinase activity and ERK (extracellular signal-regulated kinase) phosphorylation and induces expression of the cell cycle inhibitors p21 and p27, leading to less endothelial proliferation. However, ICAP1 promotes endothelial survival and AKT phosphorylation. Global gene expression analyses revealed that the ICAP1 effects are mediated by strong activation of DELTA-NOTCH signaling. Active NOTCH1 or silencing of the NOTCH ligand DLL4 phenocopy the ICAP1 effects and blockade of NOTCH cleavage rescues the ICAP1-mediated defects in endothelial cells. Both ICAP1 and NOTCH1 reduce the expression of ESM1 (endothelial cell-specific molecule-1), and silencing of ESM1 disturbs vascular endothelial growth factor- or fibroblast growth factor 2-induced sprouting angiogenesis.Conclusions: In this study, we identified ICAP1 as a novel regulator to prevent excessive sprouting angiogenesis. (Circ Res. 2010; 107: 592-601.)