VEGF A

Abstract

VEGF-A is the founding member of the VPF/VEGF family of proteins that also includes VEGFs B, C and D as well as PlGF (placenta growth factor) and a related viral protein, VEGF-E (Dvorak, J Clin Oncol 20:4368–4380, 2002; Am J Pathol 162:1747–1757, 2003; Ferrara et al., Nat Med 9:669–676, 2003; Mukhopadhyay et al., Vascular permeability factor/vascular endothelial growth factor and its receptors: evolving paradigms in vascular biology and cell signaling. In: Aird W (ed) The endothelium: a comprehensive reference. Cambridge University Press, Cambridge, 2007; Bry et al., Circulation 122:1725–1733, 2010; Hagberg et al., Nature 464:917–921, 2010; Shibuya and Claesson-Welsh, Exp Cell Res 312:549–560, 2006; Veikkola and Alitalo, Semin Cancer Biol 9:211–220, 1999). VEGF-A, the subject of this chapter, has critical roles in vasculogenesis and pathological and physiological angiogenesis, acting through receptors (VEGFR-1, VEGFR-2 and neuropilin) that are expressed on vascular endothelium as well as on certain other cell types (Fig. 1) (Shibuya and Claesson-Welsh, Exp Cell Res 312:549–560, 2006; Veikkola and Alitalo, Semin Cancer Biol 9:211–220, 1999; Bielenberg et al., Exp Cell Res 312:584–593, 2006). The product of a single gene, VEGF-A is alternatively spliced to form several proteins of different lengths, properties and functions. Originally discovered as a potent vascular permeabilizing factor (VPF) (Senger et al., Science 219:983–985, 1983; Dvorak et al., J Immunol 122:166–174, 1979), VEGF-A is also an endothelial cell motogen and mitogen, profoundly alters the pattern of endothelial cell gene expression, and protects endothelial cells from apoptosis (Benjamin et al., J Clin Invest 103:159–165, 1999) and senescence (Dvorak, Am J Pathol 162:1747–1757, 2003). Recently, VEGF-A has been found to have additional critical roles in hematopoiesis and in expansion and differentiation of bone marrow endothelial cell precursors (Seandel et al., Cancer Cell 13:181–183, 2008), in maintenance of the nervous system (Ruiz de Almodovar et al., Physiol Rev 89:607–648, 2009), and in development. Mice lacking even one copy of the VEGF-A gene are embryonic lethal (Ferrara et al., Nat Med 9:669–676, 2003; Carmeliet, Nat Med 9:653–660, 2003). VEGFs C and D are essential for development of the lymphatic system (Veikkola and Alitalo, Semin Cancer Biol 9:211–220, 1999), VEGF-B has a role in the development of coronary arteries and in fatty acid metabolism (Bry et al., Circulation 122:1725–1733, 2010; Hagberg et al., Nature 464:917–921, 2010), and PlGF has important roles in pathological angiogenesis (Carmeliet, Nat Med 9:653–660, 2003; Luttun et al., Nat Med 8:831–840, 2002). VEGF-A also induces abnormal lymphangiogenesis (Nagy et al., J Exp Med 196:1497–1506, 2002).