Angiogenesis alteration by defibrotide: implications for its mechanism of action in severe hepatic veno-occlusive disease

摘要: Defibrotide (DF) is a mixture of porcine-derived single-stranded phosphodiester oligonucleotides (9-80-mer; average, 50-mer) that has been successfully used to treat severe hepatic veno-occlusive disease (sVOD) with multiorgan failure (MOF) in patients who have received cytotoxic chemotherapy preparation for bone marrow transplantation. However, its mechanism action unknown. Herein, we show DF and can bind heparin-binding proteins (eg, basic fibroblast growth factor [bFGF] but not vascular endothelial [VEGF] 165) low nanomolar affinity. This binding occurred length- concentration-dependent manner. mobilize proangiogenic factors such as bFGF from their depot or storage sites on bovine corneal matrix. these molecules do interfere high-affinity FGFR1 IIIc replace heparin required cofactor hence cellular mitogenesis. also protects against digestion by trypsin chymotrypsin air oxidation. In addition, binds collagen I affinity promote human microvascular cell-1 (HMEC-1) cell mitogenesis tubular morphogenesis three-dimensional gels. Thus, our data suggest may provide stimulus the sinusoidal endothelium liver suffered angiotoxic event, thus helping ameliorate clinical sVOD/MOF syndrome.