Re-evaluating therapeutic neovascularization.

Numerous animal studies have established that neo-vascularization of ischemic tissue can be enhanced with exogenous growth factors and small clinical studies have shown encouraging results. However, the two largest randomized clinical trials to date were negative. Mechanistically, the major stimuli for neo-vascularization are hypoxia and inflammation. Hypoxia-inducible-factor (HIF-1) is a 'master switch' protein that is generated in response to hypoxia and binds to more than 40 hypoxia sensitive genes, inducing a panoply of angiogenic and protective metabolic responses. Inflammatory signals recruit T-lymphocytes and macrophages into areas of neo-vascularization which act as a source of angiogenic and arteriogenic factors. Although hypoxia and inflammation are interdependent in eliciting neo-vascular responses, angiogenesis appears to be hypoxia-dependent, whereas inflammation and hemodynamic factors drive arteriogenesis. The negative outcome of the two largest trials may have many reasons. There are issues relating to patient selection, choice of growth factor therapy, dosing and route administration, concomitant medication, trial design including the efficacy parameters that were selected and a lack of sufficient insight into the mechanisms that are responsible for neo-vascularization. In order to move forward the therapeutic objective should be switched to arteriogenesis although this process is even more poorly understood than angiogenesis. Genetic studies in mice with intrinsically different arteriogenic responses combined with studies in human populations with differences in the extent of collateral development may provide fundamental insight into arteriogenic mechanisms. Attention should also be focused on the way in which arteriogenesis is stimulated and the endpoints of clinical trials should be redefined.