Critical role of microenvironmental factors in angiogenesis.

Therapeutic angiogenesis, which entails the induction of new blood vessels by the delivery of angiogenic growth factors, is a highly attractive approach to the treatment of ischemic diseases. However, it is becoming increasingly clear that this is not easily achieved, as the effects of angiogenic growth factors can differ markedly depending on the timing of their expression, on the shape of the concentration gradients they form in vivo, and the inter-actions between endothelial cells and pericytes they induce. In fact, the same dose of vascular endothelial growth factor can induce stable, nonleaky, pericyte-covered normal capillaries or aberrant vascular structures that develop into hemangiomas. This difference in outcome can be due solely to the spatial characteristics of the delivery method. If delivery allows a homogeneous spatial distribution of VEGF in the microenvironment around each producing cell, angiogenesis can be therapeutic, whereas if the total dose is the average of diverse spatial levels, aberrant angiogenesis cannot be avoided. To achieve therapeutic angiogenesis, a means of regulating the microenvironmental levels of angiogenic factors will be critical to the generation of effective new treatment strategies.