Integrin signaling is critical for pathological angiogenesis.
J Exp Med
; 203(11): 2495-507, 2006 Oct 30.
Article
em En
| MEDLINE
| ID: mdl-17030947
ABSTRACT
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 beta3 integrin unable to undergo tyrosine phosphorylation. Two distinct models of pathological angiogenesis revealed that neovascularization is impaired in mutant beta3 knock-in mice. In an ex vivo angiogenesis assay, mutant beta3 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 beta3 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 beta3 integrin in wild-type but not in mutant beta3 knock-in endothelial cells. Moreover, phosphorylation of VEGF receptor-2 was significantly reduced in cells expressing mutant beta3 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Integrina beta3
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Neovascularização Patológica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article