Development of new method of therapeutic angiogeneis using sustained-release of multiple growth factors.

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We have reported so far that sustained-release of basic fibroblast growth factor (bFGF) augments tissue reperfusion and functional improvement both in animal models of myocardial infarction and hindlimb ischemia. However, sustained-release of bFGF alone is not sufficient to generate stable blood vessels. Moreover, in the clinical situations, presence of diabetus or hypercholesterolemia may hamper the angiogenic effect of bFGF. To overcome these problems, we investigated the effects of adjuvant thearapies combined with sustained-release of bFGF.In the present study, we have found that combined treatment with sustained-release bFGF and heparin synergistically enhances neovascularization in the hindlimb ischemia of hypercholesterolemic mice with impaired angiogenic responses to the ischemic stimulus. We are also reporting that 5HT receptor blocker, sarpogrerate has similar effect in diabetic rats. We also demonstrated that the sustained dual release of a lower dose of bFGF and hepatocyte growth factor (HGF) achieve equivalent tissue reperfusion and more mature vasculature in the ischemic limb than a higher dose of bFGF or HGF alone.Using a rat model of chronic myocardial infarction, we demonstrated the sustained-release of erythropoietin improved left ventricular function without inducing polycythemia. We also examined the effect of sustained-release of granulocyte colony stimulating factor (G-CSF), which revealed no significant improvement compared with control.From these results, we are designing clinical protocols of therapeutic angiogenesis to treat limb ischemia and choronic myocardial ischemia.