Exploring evolutional origins of viper venom haemorrhagic factors

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Snake venoms are classified mainly into two categories : neurotoxic and hemorrhagic venoms. This study addressed questions on the latter venom, what are the evolutional origins of viper hemorrhagic venom proteins or how vipers acquired them during evolution. Viper haemorrhagic factors are produced as precursor soluble factors composed of two toxic polypeptide domains, a domain of haemorrhagic activity and that of anti-coagulation activity. The precursors are similar in structure to transmembrane proteins generically named as ADAMs(a disintegrin and metalloproteases). We hypothesized that viper venoms mimicked ADAMs of ancestral vertebrates that carried functions in vasculogenesis/angiogenesis and/or behaviors of blood cells. We previously showed that ADAM8 is involved in the onset of blood circulation in zebrafish embryos by live imaging of their blood vessels and erythroblasts(Iida et al., Curr Biol., 2010.). By using this imaging technique, we examined how viper venom haemorrhagic venoms affects vasculogenesis or integrity of blood vessels, As a result, we found that some of them inhibited vasculogenesis of zebrafish embryos. Then we examine whether ADAM8 ply some roles on blood vessel formation. Injection of antisense morpholino oligonucleotides against ADAM8 into eggs caused inhibitory effects on elongation of intersegmental vessels. Live imaging and electron micrographs of those embryos revealed that blood cells attached to blood vessels abnormally and gene expression in blood vessels was significantly altered in those embryos. Haemorrhagic activities of viper venom proteins could be related to regulatory roles of ADAM8 in vasculogenesis.