factors and cytokines. Akt then phosphorylates and inhibits Bad and caspase-9, proteins known to play a major role in promoting apoptosis. The importance of Akt in VEGF’s survival effects are supported by experiments using dominant-negative mutant of Akt (DN-Akt). Overexpression of DN-Akt in endothelial cells completely blocked VEGF’s survival effects; pharmacologic inhibition of PI3-kinase achieved the same effect (87).

Although ERK1/2, PKC, and Akt have received particular attention with respect to VEGF signaling, it is likely that other signaling pathways contribute to VEGF’s effects in stimulating angiogenesis. VEGF activates multiple other signaling molecules, including p38 mitogen-activated protein kinase, Src, and calcineurin (74). The roles of these other pathways continue to be actively investigated.

OTHER ACTIONS OF VEGF

In addition to its initially demonstrated effects on vascular permeability and angiogenesis, there has been an increasing awareness that VEGF has additional effects as well. A consideration of these effects is important, both to fully realize the therapeutic potential of strategies targeting VEGF as well as the potential adverse effects.

Proinflammatory Effects of VEGF

VEGF has been found to have several proinflammatory properties, and this aspect of VEGF biology has received considerable attention with regard to diabetic retinopathy. As discussed earlier, VEGF is a very potent stimulator of vascular permeability (20). VEGF acts directly on retinal endothelial cells to stimulate permeability (80, 81), and intravitreous injections of VEGF promote blood–retinal barrier breakdown (88). In an animal model, diabetes-induced blood retinal barrier breakdown was inhibited in a dose-dependent fashion by VEGF-TrapA40, a fusion protein that contains binding domains from the VEGF receptors (89). Intravitreal injections of VEGF increases retinal ICAM-1 levels (90), and diabetes-induced increase in retinal ICAM-1 in an animal model was significantly reduced by treatment with VEGF-TrapA40. VEGF plays a significant role in promoting leukocyte adhesion in the retinal vasculature (91). In light of the possible role of proinflammatory pathways in the progression of diabetic retinopathy, these proinflammatory properties of VEGF could have important therapeutic implications (for a detailed discussion, see Chap. 13).

VEGF and Retinal Neuronal Development

The possible role of VEGF in the neural retinal development was raised by the identification of VEGF receptor expression in nonvascular cells of the retina. In developing mice, VEGFR1 mRNA was initially detected at postnatal Day 7 (P7) in the avascular retina, localized to the developing ganglion cell layer and inner nuclear layer. From P12 to P15, VEGFR1 mRNA was found in the inner nuclear layer and outer nuclear layer, consistent with a pattern of expression in Muller cells. VEGFR2 mRNA was first detected at P5, localized to the inner retinal layers. VEGFR2 mRNA was observed in the inner nuclear layer at P7 and in the inner and outer nuclear layers at P15. From P17 to P33, VEGFR1 and R2 became more localized in a vascular pattern, although VEGF receptor