The rational phase of therapeutic angiogenesis.

Largely disappointing results from early clinical trials have settled down the initial unrealistic hope that fueled therapeutic angiogenesis. Now that this research has reached a rational phase, every concept in the theory of neo-vascularization needs to be re-evaluated. Neo-vascularization in adult tissues has been described as the result of either arteriogenesis, angiogenesis or vasculogenesis. The contribution of these mechanisms to neo-vascularization in vivo can likely not be separated experimentally. All currently known growth factors are pleiotropic and induce the secondary release of other growth factors. A complete analysis of the efficacy of growth factors therefore should include parameters of arteriogenesis, angiogenesis and vasculogenesis. Current clinical studies have likely suffered from drug regimens with short exposure of a single growth factor. Although combinations of growth factors may be theoretically appealing to create robust sustained neo-vessels, preclinical and clinical study designs may become too complex. Instead, there is some evidence that prolonged exposure to a single growth factor might result in vessels that are resistant to regression. With the vast and rapidly growing body of data that is being obtained on growth factors and pro-angiogenic strategies, approaches will emerge that are more effective than the ones presently tested in the clinic. It remains imperative however, that these approaches are rationally based on fundamental and preclinical data.