Vascular endothelial cell growth factor-a: not just for endothelial cells anymore.

When vascular endothelial cell growth factor-A (VEGF-A) was first identified as an endothelial cell mitogen and vascular permeability factor, it was thought to be a specific mitogen for endothelial cells, and its main signaling receptors, VEGFR2/Flk1/KDR and VEGFR1/Flt-1, were reported to be expressed solely by the endothelium. On what was this claim based? First, early studies with newly described growth factors are usually focused almost exclusively in the initial field of discovery (eg, VEGF-A and the vasculature). Second, in the early days of a growth factor’s characterization, reagents are limiting—they may not be very accessible or of particularly good quality. Once a growth factor is better characterized and reagents improve in quality and sensitivity (eg, antisera for immunohistochemical localization of receptors and development of gene-reporter transgenic mice), more comprehensive and reliable analyses of expression and actions are possible. Finally, and perhaps more importantly, growth factors are often named for the activity on which they were first identified: for VEGF-A, its ability to induce vascular endothelial cell proliferation. The naming of a factor to reflect its identifying activity is an historical pattern in the designation of peptide growth factors and cytokines including, for example, fibroblast growth factor, epidermal growth factor, and hepatocyte growth factor. It seems then that the simple labeling of a factor limits, at least initially, consideration of activities outside of that implied by its name. For VEGF-A, the belief that its activities were specific to the vasculature were likely to have been further enforced by the observation of its critical and central role during vascular development: targeted disruption of even a single VEGF-A allele leads to the total disruption of vascular development and early embryologic lethality.1,2 Perhaps, then, it was just a matter of time before the pluripotent nature of VEGF-A began to be revealed. The most significant findings outside of the vasculature relates to the role of VEGF-A in the neural system. VEGF-A has been previously demonstrated to be neuroprotective in models of ischemic/hypoxic injury in the central nervous system (see reviews3,4) and now in the retina, as described in the article by Nishijima et al5 in this issue of The American Journal of Pathology. A variety of activities have been suggested to account for the observed neuroprotection, including enhancement of axonal regeneration,6 inhibition of caspase-3, and enhancement of neurogenesis in the subventricular and subgranular zones7 as well as activation of Akt.8 In addition, decreased VEGF-A levels via deletion of the hypoxia-response element in the VEGF-A promoter led to progressive degeneration of motor neurons due, at least in part, to reduced action on VEGFR2-expressing motor neurons.9 Despite this growing body of data demonstrating significant effects of VEGF-A on neural cells, very little is known about the role of VEGF-A in neural retina. Considering the widespread use of VEGF-A-neutralizing therapies in the treatment of macular edema and choroidal neovascularization associated with the wet form of age-related macular degeneration (AMD),10 the lack of knowledge regarding the role of VEGF-A on neural retina represents a particularly serious information gap. VEGF-A clearly plays a role in the developmental vascularization of the retina, where it both directs angiogenic ingrowth11 and acts as a survival factor.12 A few early reports also suggested a nonvascular role for VEGF-A in the retina. Retinal progenitors express VEGFR2,13 and exogenously added VEGF-A induces the differentiation of photoreceptor cells in vitro14 as well as neurite outgrowth from postnatal retinal explants.15 In the adult retina, VEGF-A is produced by pericytes and astrocytes,16 Muller glial cells, amacrine cells, and ganglion cells17 as well as by the retinal pigment epithelial cells.18 However, data regarding a function for VEGF-A in the adult—on either vascular or nonvascular cells—are lacking. In the article by Nishijima et al5 in this issue of the AJP, this topic is addressed with the demonstration of a very compelling and timely role for VEGF-A in neural retinal survival. In a retinal model of ischemia-reperfusion injury, the authors demonstrate a dose-dependent ability of VEGF-A to prevent neural cell death. They further show that ischemic preconditioning leads to elevated VEGF-A, which in turn decreases neural retinal cell death, and that blocking VEGF-A in this model leads to increased neural cell death. Finally, the authors report that neutralization of VEGF-A by both systemic and local delivery of inhibitors for 8 weeks leads to retinal ganglion cell death. The report by Nishijima et al5 highlights two evolving stories that relate to the biological activity of VEGF-A: first, that it acts on cells outside of the vasculature, and second, that it plays a significant role in the adult.