Vascular Endothelial Growth Factor and the Angiopoietins

Abstract

Angiogenesis is a complex multistep process by which new blood vessels are formed from the preexisting vasculature.1 2 Angiogenesis is a crucial event in normal embryonic development, and it contributes to the development and progression of a number of diseases, including cancer, arthritis, and diabetes. Conversely, insufficient growth of collateral vessels is a major clinical problem in atherosclerotic cardiovascular disease. The involvement of angiogenesis, or the failure of angiogenesis, in these important diseases has created a tremendous effort to define the molecular mechanisms by which the process is driven. Until recently, most of the work in the field has focused on polypeptide growth factors, such as fibroblast growth factor and vascular endothelial growth factor (VEGF), which are mitogenic for endothelial cells in vitro and produce an angiogenic response in vivo. Angiopoietins (Ang1 and Ang2) constitute a novel family of endothelial growth factors that are ligands for the endothelium-specific receptor tyrosine kinase, Tie2.3 Unlike other endothelial growth factors, stimulating Tie2 in cultured endothelial cells with either Ang1 or Ang2 does not produce a mitogenic response.3 Similar to other angiogenic factors, however, Ang1 can stimulate endothelial sprouting in vitro.4 Complicating matters, Ang2 appears to block the activation of Tie2 by Ang1, suggesting that it may be a naturally occurring inhibitor of Ang1/Tie2 activity.5 Despite the inability of angiopoietins to stimulate endothelial mitogenesis, disrupting the function of either Tie2 or Ang1 in transgenic mice resulted in early embryonic lethality secondary to defects in the developing vasculature.6 7 8 The defects included a decreased number of endothelial cells, simplification of the vascular branching pattern, and failure to recruit pericytes and smooth muscle cells. Consistent with its action as an Ang1/Tie2 inhibitor, overexpression of Ang2 resulted in vascular defects similar to those in the Ang1 or Tie2 knockouts.5 Taken together, these studies suggested that unlike other angiogenic growth factors, such as VEGF, which function during the earliest stages of vascular development, the angiopoietins play their major role at later stages of vascular development, ie, during vascular remodeling and maturation.