Angiogenesis: Basic Mechanisms and Clinical Applications

Abstract

The development and maintenance of an adequate vascular supply is critical for the viability of normal and neoplastic tissues. Angiogenesis, the development of new blood vessels from preexisting capillary networks, plays an important role in a number of physiologic and pathologic processes, including reproduction, wound repair, inflammatory diseases, and tumor growth. Angiogenesis involves sequential steps that are triggered in response to angiogenic growth factors released by inflammatory, mesenchymal, or tumor cells that act as ligands for endothelial cell receptor tyrosine kinases. Stimulated endothelial cells detach from neighboring cells and migrate, proliferate, and form tubes. The immature tubes are subsequently invested and stabilized by pericytes or smooth muscle cells. Angiogenesis depends upon complex interactions among various classes of molecules, including adhesion molecules, proteases, structural proteins, cell surface receptors, and growth factors. The therapeutic manipulation of angiogenesis targeted against ischemic and neoplastic diseases has been investigated in preclinical animal models and in clinical trials. Proangiogenic trials that have stimulated vessel growth in ischemic coronary or peripheral tissues through expression, delivery, or stimulated release of growth factors have shown efficacy in animal models and mixed results in human clinical trials. Antiangiogenic trials have used strategies to block the function of molecules critical for new vessel growth or maturation in the treatment of a variety of malignancies, mostly with results less encouraging than those seen in preclinical models. Pro-and antiangiogenic clinical trials demonstrate that strategies for optimal drug delivery, dosing schedules, patient selection, and endpoint measurements need further investigation and refinement before the therapeutic manipulation of angiogenesis will realize its full clinical potential.