The existence of angiogenic factors was initially postulated on the basis of the strong neovascular response induced by transplanted tumors. Subsequently, it was shown that normal tissues are also a source of angiogenic activity. Many molecules have been implicated as positive regulators of angiogenesis, including acidic fibroblast growth factor (FGF), basic FGF, transforming growth factor (TGF)-ฮฑ, TGF-ฮฒ, hepatocyte growth factor (HGF, or scatter factor), tumor necrosis factor-ฮฑ, angiogenin, interleukin (IL)-8 and the angiopoietins 1,2 .For over a decade, the role of VEGF (also referred to as VEGFA) in the regulation of angiogenesis was the object of intense investigation (see ref. 3 for a historic overview of the VEGF field). Recent evidence indicates that new vessel growth and maturation are highly complex and coordinated processes, requiring the sequential activation of a series of receptors by numerous ligands (reviewed in refs. 2,4,5), but VEGF signaling often represents a critical rate-limiting step in physiological angiogenesis. VEGF also seems to be important in pathological angiogenesis, such as that associated with tumor growth . VEGF belongs to a gene family that includes placental growth factor (PLGF), VEGFB, VEGFC and VEGFD. Homologs of VEGF have also been identified in the genome of the parapoxvirus Orf virus and shown to have VEGF-like activities 6,7 . This review focuses on the biology of the prototype member, VEGFA, a key regulator of blood vessel growth. VEGFC and VEGFD regulate lymphatic angiogenesis 8 , emphasizing the unique role of this family in controlling growth and differentiation of multiple anatomic components of the vascular system.
Activities of VEGF
A well-documented in vitro activity of VEGF is the ability to promote growth of vascular endothelial cells (ECs) derived from arteries, veins and lymphatics (reviewed in ref. ). VEGF induces a potent angiogenic response in a variety of in vivo models . VEGF delivery also induces lymphangiogenesis in mice 11 . Although ECs are the primary target of VEGF, several studies have reported mitogenic effects on certain non-EC types (reviewed in ref. 12). Recent studies have also shown that VEGF stimulates surfactant production by alveolar type II cells .VEGF is a survival factor for ECs, both in vitro and in vivo . In vitro, VEGF prevents apoptosis induced by serum starvation. Gerber et al. have shown that such activity is mediated by the phosphatidylinositol (PI)-3 kinase-Akt pathway 15 . VEGF also induces expression of the anti-apoptotic proteins Bcl-2 and A1 in endothelial cells .In vivo, the prosurvival effects of VEGF are developmentally regulated. VEGF inhibition results in extensive apoptotic changes in the vasculature of neonatal but not adult mice . Furthermore, a marked VEGF dependence has been shown in endothelial cells of newly formed but not of established vessels within tumors . Coverage by pericytes has been proposed to be one of the key events resulting in loss of VEGF dependence .VEGF has also effects on bone marrow-derived cells. It promotes monocyte chemotaxis and induces colony formation by mature subsets of granulocyte-macrophage progenitor cells 20 . VEGF delivery to adult mice inhibits dendritic cell development 21 and increases production of B cells and generation of immature myeloid cells . Conditional gene knock-out technology has been used to achieve selective VEGF gene ablation in bone-marrow cell isolates and hematopoietic stem cells (HSCs) . VEGF-deficient HSCs and bonemarrow mononuclear cells did not repopulate lethally irradiated hosts, despite the coadministration of a large excess of wild-type cells. These studies also pointed to an internal autocrine loop, not blocked by extracellular inhibitors such as antibodies, by which VEGF controls HSC survival during hematopoietic repopulation .VEGF is known also as vascular permeability factor, based on its ability to induce vascular leakage . It is now well established that such permeability-enhancing activity underlies significant roles of this molecule in inflammation and other pathological circumstances. VEGF induces an increase in hydraulic conductivity of isolated microvessels; this effect is mediated by increased calcium influx . Consistent with a role in the regulation of vascular permeability, VEGF induces endothelial fenestration in some vascular beds .VEGF induces vasodilatation in vitro in a dose-dependent fashion as a result of endothelial cell-derived nitric oxide 28 , and produces tran-