Regulation of vascular permeability by vascular endothelial growth factors

Increased vascular permeability is one of the first stages in both physiological and pathological angiogenesis—the generation of new blood vessels from preexisting vasculature. Although this has been hypothesised to be true in physiological angiogenesis, it is clearly a mark of blood vessel growth in disease. Normal, healthy blood vessel growth ( physiological angiogenesis) occurs throughout development as well as during tissue repair and growth in adult tissues. Angiogenesis is also seen in a wide variety of diseases, which include all the major causes of mortality in the West—heart disease, cancer, stroke, vascular disease, and diabetes. Much of this angiogenesis is significantly different from normal blood vessel growth and is termed pathological angiogenesis. Angiogenesis is regulated by vascular growth factors, the most notable being the vascular endothelial growth factor family of proteins (VEGF). These act on specific receptors in the vascular system to stimulate new vessel growth by a number of mechanisms. VEGFs also directly stimulate increased vascular permeability to water and large molecular weight proteins and vasodilatation. These two effects result in a large flux of water and macromolecules from the vasculature to the interstitium, often resulting in oedema. This review will outline the mechanisms by which VEGFs do this and discuss some of the difficulties in interpreting data from VEGF studies due to the conflicting and synergistic effects of these actions.