The role of alphav integrins during angiogenesis (original) (raw)
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Angiogenesis induced by tumor necrosis factor-agr; is mediated by alpha4 integrins
Angiogenesis, 1998
Tumor necrosis factor-alpha (TNF-alpha) and fibroblast growth factor-2 (FGF-2 or bFGF) are potent stimulators of angiogenesis. TNF- alpha, but not FGF-2, can induce the expression of vascular cell adhesion molecule-1 (VCAM-1) on the surface of endothelial cells. The soluble form of VCAM-1 has recently been demonstrated to function as an angiogenic mediator. Here we demonstrate that monoclonal antibodies directed against VCAM-1 or its alpha4 integrin counter- receptor inhibited TNF-alpha-induced endothelial cell migration in vitro. Angiogenesis induced in vivo in rat corneas by TNF-alpha was inhibited by a neutralizing antibody directed against the rat alpha4 integrin subunit. A peptide antagonist of the a4 integrins blocked TNF-alpha-induced endothelial cell migration in vitro and angiogenesis in rat corneas in vivo. No inhibition by the antibodies or peptide antagonist was observed either in vitro or in vivo when FGF-2 was used as the stimulus. The peptide antagonist did not inhibi...
Angiogenesis induced by tumor necrosis factor-agr; is mediated by a4 integrins
Angiogenesis, 1998
Tumor necrosis factor-a (TNF-a) and ®broblast growth factor-2 (FGF-2 or bFGF) are potent stimulators of angiogenesis. TNF-a, but not FGF-2, can induce the expression of vascular cell adhesion molecule-1 (VCAM-1) on the surface of endothelial cells. The soluble form of VCAM-1 has recently been demonstrated to function as an angiogenic mediator. Here we demonstrate that monoclonal antibodies directed against VCAM-1 or its a4 integrin counter-receptor inhibited TNF-a-induced endothelial cell migration in vitro. Angiogenesis induced in vivo in rat corneas by TNF-a was inhibited by a neutralizing antibody directed against the rat a4 integrin subunit. A peptide antagonist of the a4 integrins blocked TNF-a-induced endothelial cell migration in vitro and angiogenesis in rat corneas in vivo. No inhibition by the antibodies or peptide antagonist was observed either in vitro or in vivo when FGF-2 was used as the stimulus. The peptide antagonist did not inhibit TNF-a binding to its receptor nor did it block the function of avb3, an integrin previously implicated in TNF-a and FGF-2 mediated angiogenesis. These results demonstrate that angiogenic processes induced by TNF-a are mediated in part by a4 integrins possibly by a mechanism involving the induction of soluble VCAM-1.
Angiogenesis induced by tumor necrosis factor-agr; is mediated by α4 integrins
Angiogenesis, 1998
Tumor necrosis factor-α (TNF-α) and fibroblast growth factor-2 (FGF-2 or bFGF) are potent stimulators of angiogenesis. TNF-α, but not FGF-2, can induce the expression of vascular cell adhesion molecule-1 (VCAM-1) on the surface of endothelial cells. The soluble form of VCAM-1 has recently been demonstrated to function as an angiogenic mediator. Here we demonstrate that monoclonal antibodies directed against VCAM-1
Endothelial cell integrin α 5 β 1 expression is modulated by cytokines and during migration in vitro
1999
The formation of new capillary blood vessels, or angiogenesis, is an absolute requirement for the growth and repair of normal tissues, and is the process by which new blood vessels are formed in hemangiomas, proliferative retinopathy and rheumatoid arthritis. Angiogenesis is also necessary for tumor growth, and is required for the hematogenous dissemination of tumor cells and the growth of metastasis (reviewed by Folkman, 1995; Pepper et al., 1997a). Angiogenesis proceedes through two phases. The first is the activation phase, which includes increased vascular permeability and extravascular fibrin deposition, basement membrane degradation, cell migration and extracellular matrix invasion, endothelial cell proliferation and capillary lumen formation. The second is the resolution phase, which includes inhibition of endothelial cell proliferation, cessation of migration, basement membrane reconstitution and junctional complex maturation (Pepper et al., 1996). Many of these processes ar...
Journal of Biological Chemistry, 2011
Integrin ␣91 mediates accelerated cell adhesion and migration through interactions with a number of diverse extracellular ligands. We have shown previously that it directly binds the vascular endothelial growth factors (VEGF) A, C, and D and contributes to VEGF-induced angiogenesis and lymphangiogenesis. Until now, the ␣91 binding site in VEGF has not been identified. Here, we report that the three-amino acid sequence, EYP, encoded by exon 3 of VEGF-A is essential for binding of VEGF to integrin ␣91 and induces adhesion and migration of endothelial and cancer cells. EYP is specific for ␣91 binding and neither requires nor activates VEGFR-2, the cognate receptor for VEGF-A. Following binding to EYP, integrin ␣91 transduces cell migration through direct activation of the integrin signaling intermediates Src and focal adhesion kinase. This interaction is biologically important because it mediates in vitro endothelial cell tube formation, wound healing, and cancer cell invasion. These novel findings identify EYP as a potential site for directed pharmacotherapy. EXPERIMENTAL PROCEDURES Materials-Human VEGF-A165 (Sf 21 (baculovirus)-derived, Ala 27-Arg 191 , disulfide-linked homodimer, 19-21 kDa) and phycoerythrin-conjugated monoclonal anti-human VEGFR-2/KDR antibodies were purchased from R&D Systems (Minneapolis, MN); Src inhibitor, PP1, was obtained from Biomol (Plymouth Meeting, PA). Mouse monoclonal antibody to integrin ␣91 (NC-4) and TNfn3RAA (RAA), a specific ligand for integrin ␣91 (17, 18), were kindly provided by Dr.