Integrin signaling is critical for pathological angiogenesis.
Integrin signaling is critical for pathological angiogenesis.
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整联蛋白信号传导对于病理血管生成至关重要。
DOI：
10.1084/jem.20060807
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发表时间：
2006-10-30
影响因子：
15.3
通讯作者：
Byzova, Tatiana V.
中科院分区：
文献类型：
--
作者：
Mahabeleshwar, Ganapati H.;Feng, Weiyi;Phillips, David R.;Byzova, Tatiana V.
出生后血管生成的过程在许多疾病的发病机制中起关键作用，包括但不限于肿瘤生长/转移、糖尿病性视网膜病变和损伤后的组织重塑。然而，这一复杂过程背后的分子事件还没有得到很好的理解，许多问题仍然存在争议，包括整合素受体的调节功能。为了分析整合素磷酸化和信号传导在血管生成中的作用，我们产生了表达不能进行酪氨酸磷酸化的突变β3整合素的敲入小鼠。两种不同的病理性血管生成模型显示，在突变β3基因敲入小鼠中，新血管形成受损。在离体血管生成试验中，突变β3敲入内皮细胞对血管内皮生长因子（VEGF）刺激没有形成完整的毛细血管。在细胞水平，突变β3基因敲入细胞中酪氨酸磷酸化缺陷导致内皮细胞粘附、铺展和迁移受损。在分子水平上，VEGF刺激野生型内皮细胞中VEGF受体-2和β3整合素之间的复合物形成，但在突变型β3敲入内皮细胞中不刺激。此外，与野生型相比，表达突变型β3的细胞中VEGF受体-2的磷酸化显著降低，导致这些细胞中整合素活化受损。这些发现为整合素-VEGF轴在病理性血管生成中的作用提供了新的机制见解。
The process of postnatal angiogenesis plays a crucial role in pathogenesis of numerous diseases, including but not limited to tumor growth/metastasis, diabetic retinopathy, and in tissue remodeling upon injury. However, the molecular events underlying this complex process are not well understood and numerous issues remain controversial, including the regulatory function of integrin receptors. To analyze the role of integrin phosphorylation and signaling in angiogenesis, we generated knock-in mice that express a mutant β3 integrin unable to undergo tyrosine phosphorylation. Two distinct models of pathological angiogenesis revealed that neovascularization is impaired in mutant β3 knock-in mice. In an ex vivo angiogenesis assay, mutant β3 knock-in endothelial cells did not form complete capillaries in response to vascular endothelial growth factor (VEGF) stimulation. At the cellular level, defective tyrosine phosphorylation in mutant β3 knock-in cells resulted in impaired adhesion, spreading, and migration of endothelial cells. At the molecular level, VEGF stimulated complex formation between VEGF receptor-2 and β3 integrin in wild-type but not in mutant β3 knock-in endothelial cells. Moreover, phosphorylation of VEGF receptor-2 was significantly reduced in cells expressing mutant β3 compared to wild type, leading to impaired integrin activation in these cells. These findings provide novel mechanistic insights into the role of integrin–VEGF axis in pathological angiogenesis.
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DOI：
10.1083/jcb.143.7.2081
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Byzova TV;Plow EF
通讯作者：
Plow EF
影响因子：
3.3
作者：
Boettiger, D;Huber, F;Blystone, S
通讯作者：
Blystone, S
影响因子：
4
作者：
Chandhoke, SK;Williams, M;Blystone, SD
通讯作者：
Blystone, SD
影响因子：
82.9
作者：
Chen, JH;Somanath, PR;Byzova, TV
通讯作者：
Byzova, TV
影响因子：
64.5
作者：
BROOKS, PC;MONTGOMERY, AMP;CHERESH, DA
通讯作者：
CHERESH, DA