Evaluation of the anti-angiogenic properties of the new selective α(V)β(3 )integrin antagonist RGDechiHCit

BACKGROUND: Integrins are heterodimeric receptors that play a critical role in cell-cell and cell-matrix adhesion processes. Among them, α(V)β(3 )integrin, that recognizes the aminoacidic RGD triad, is reported to be involved in angiogenesis, tissue repair and tumor growth. We have recently synthesized a new and selective ligand of α(V)β(3 )receptor, referred to as RGDechiHCit, that contains a cyclic RGD motif and two echistatin moieties. METHODS: The aim of this study is to evaluate in vitro and in vivo the effects of RGDechiHCit. Therefore, we assessed its properties in cellular (endothelial cells [EC], and vascular smooth muscle cells [VSMC]) and animal models (Wistar Kyoto rats and c57Bl/6 mice) of angiogenesis. RESULTS: In EC, but not VSMC, RGDechiHCit inhibits intracellular mitogenic signaling and cell proliferation. Furthermore, RGDechiHCit blocks the ability of EC to form tubes on Matrigel. In vivo, wound healing is delayed in presence of RGDechiHCit. Similarly, Matrigel plugs demonstrate an antiangiogenic effect of RGDechiHCit. CONCLUSIONS: Our data indicate the importance of RGDechiHCit in the selective inhibition of endothelial α(V)β(3 )integrin in vitro and in vivo. Such inhibition opens new fields of investigation on the mechanisms of angiogenesis, offering clinical implications for treatment of pathophysiological conditions such as cancer, proliferative retinopathy and inflammatory disease.