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 aFGF, bFGF, TGF-α TGF-β, HGF/SF, TNF-α, angiogenin, IL-8, the angiopoietins, etc.[1, 2].

For over a decade, the role of vascular endothelial growth factor (VEGF) in the regulation of angiogenesis had been object of intense investigation. For a historic overview of the VEGF field, see [3]. While 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 (for reviews see [2, 4, 5]), there is consensus that VEGF signaling often represents a critical rate-limiting step in physiological angiogenesis. VEGF appears to be also important in pathological angiogenesis, such as that associated with tumor growth [6]. VEGF (referred to also as VEGF-A) belongs to a gene family that includes placenta growth factor (PlGF)[7], VEGF-B [8], VEGF-C [9, 10], and VEGF-D [11]. Additionally, homologues of VEGF have been identified in the genome of the parapoxvirus Orf virus [12] and shown to have VEGF-like activities [13]. The main focus of this review is the biology of the prototype member, VEGF-A, a key regulator of blood vessel growth. Importantly, VEGF-C and VEGF-D regulate lymphatic angiogenesis [14], emphasizing the unique role played by this gene family in controlling growth and differentiation of multiple anatomic components of the vascular system.