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Ding S, Merkulova-Rainon T, Han ZC et al.HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Blood 101:4816-4822

Institut des Vaisseaux et du Sang, Centre de Recherche de l'Association Claude Bernard, Paris, France.
Blood (Impact Factor: 10.43). 07/2003; 101(12):4816-22. DOI: 10.1182/blood-2002-06-1731
Source: PubMed

ABSTRACT Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic growth factor and a powerful stimulator of angiogenesis, which acts on cells by binding to the c-met receptor. The exact role of the endogenous HGF/c-met system in one or more steps of the angiogenic process is not completely understood. To contribute to this question we used immunocytochemical analysis, Western blotting, and reverse transcription-polymerase chain reaction to study the expression of c-met in endothelial cells cultured in different growth conditions. We found that c-met is not colocalized with vascular endothelial (VE)-cadherin in cell-cell junctions. c-met and VE-cadherin were shown to be inversely regulated by cell density, at both the protein and the mRNA levels. We established that c-met is up-regulated during the in vitro recapitulation of several steps of angiogenesis. The c-met expression was increased shortly after switching to angiogenic growth conditions and remained high during the very first steps of angiogenesis, including cell migration, and cell proliferation. The endothelial cells in which the expression of c-met was up-regulated were more responsive to HGF and exhibited a higher rate of morphogenesis. Moreover, the antibody directed against the extracellular domain of the c-met inhibited angiogenesis in vitro. Our results suggest that c-met is a marker of angiogenic phenotype for endothelial cells and represents an attractive target for the development of new antiangiogenic therapies.

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    • "c- Met, a tyrosine kinase receptor that binds HGF (Jiang et al. 2005), also interacts with NRP1. Hepatocyte growth factor ⁄ c-met signalling plays a vital role in the development and regeneration of several organ systems (Birchmeier et al. 2003) and regulation of endothelial cell survival, proliferation and migration (Ding et al. 2003). Recent studies have demonstrated that NRP1 and NRP2 act as a functional co-receptor for HGF, enhancing HGF ⁄ c-met binding and Figure 4 Vascular endothelial growth factor (VEGF) interaction with VEGF-R2 and neuropilin-1 (NRP-1) and downstream signalling. "
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    • "c-Met belongs to a subfamily of receptor tyrosine kinases (RTKs) [15]. The activation of c-Met has been reported to trigger cancer cell proliferation, migration and invasion [16], and promote tumor vessel angiogenesis [17] because HGF directly stimulates endothelial cell proliferation and migration [18]. Aberrant c-Met activation , including gene amplification, mutation, and overexpression, has been found in clinical cases involving hematological malignancies and most solid tumors [19]. "
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    • "HGF activates migration and proliferation of endothelial cells and induces angiogenesis . The angiogenic activity of HGF is mediated through its direct actions on endothelial cells [3] [4], and its indirect actions that occur through an increase of endothelial cell mitogens [4] [5]. Because of this angiogenic activity, HGF is known to improve coronary and peripheral artery diseases [6] [7]. "
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