The maturation of vessels : a limitation to forced neovascularization?

Therapeutic angiogenesis is the induction of new blood vessels by the delivery of appropriate growth factors and is an attractive approach to the treatment of different ischemic conditions. The experience with initial clinical trials in the past decade has shown that this may be more complex than anticipated and highlights the need to incorporate current advancements in our understanding of the regulation of vessel growth in the design of novel strategies. The generation of new capillaries from neighboring microvasculature by angiogenesis can be represented as a two-step process: 1) tube formation, in which endothelial cells respond to gradients of angiogenic factors, proliferate and migrate towards areas where increased blood flow is needed, and 2) vascular maturation, in which pericytes are recruited to proliferating endothelium and induce quiescence and stabilization of the new capillaries through cell-cell contact and paracrine factors. The formation of a new vascular network with normal morphology and physiological function requires a proper balance between these two processes. Here we will review the current understanding of how the growth of normal or pathological blood vessels is determined by growth factor gradients in the microenvironment and what lessons can be learned to design more physiological strategies to achieve therapeutic angiogenesis for the treatment of ischemia. In particular, we will discuss the possibility to exploit vascular maturation as a target distinct from vessel induction, but capable of modulating the effects of angiogenic factors, and its implications for increasing safety and efficacy of therapeutic angiogenesis strategies.