Therapeutic angiogenesis: a case for targeted, regulated gene delivery.

Blood and vascular disorders underlie a plethora of pathological conditions and are the single most frequent cause of human disease. Eliminated or restricted blood flow to tissues as a result of vessel dysfunction results in the disruption of oxygen and nutrient delivery and the accumulation of waste metabolites. Cells cannot survive extended severe ischemia but may be able to adapt to a moderate condition where diffusion to and from bordering nonischemic regions sustain vital functions. Under this condition, secondary functions of affected cells are likely to be impaired and a new metabolic equilibrium is established, determined by the level of cross-diffusion. In tissues with a normally high metabolic turnover such as skeletal and cardiac muscle, ischemia causes hypoxia, acidosis, and depressed function (contractility). The treatment possibilities for tissue ischemia resulting from vascular disease are limited. Lipid-lowering agents may help slow the progression of vessel disease in some instances, but surgical reconstruction may be the only option in advanced stages, and even this is not always an option. An alternative and rather obvious strategy to treat ischemia is to activate endogenous angiogenic or vasculogenic pathways and stimulate revascularization of the tissue. The feasibility of such a strategy has now been established through the results of studies over the past decade and a new discipline called therapeutic angiogenesis has emerged. This review focuses on the application of therapeutic angiogenesis for treating peripheral limb ischemia and coronary artery diseases; the author traces the evidence supporting the feasibility of this treatment strategy, its current limitations, and possible directions.