Table 2

Additional Physiological Processes Involving VEGF

•Bone growth

•Wound healing

•Female reproductive cycling

•Vasorelaxation

•Glomerulogenesis

•Protection of hepatic cells

•Skeletal muscle regeneration

•Neural survival factor

•Trophic support of choriocapillaris

In addition to its role as a potent endothelial cell mitogen, VEGF serves as an endothelial cell survival factor (16) and as a chemoattractant for bone marrow-derived endothelial cells (17–19). VEGF also induces the synthesis of several enzymes whose actions affect angiogenesis, including the matrix metalloproteinases and plasminogen activator (20–22). VEGF induces nitric oxide synthase, leading to upregulation of nitric oxide, a stimulator of angiogenesis (23, 24). In addition, VEGF acts as a chemoattrac-tant for monocyte lineage cells (25). which are believed to contribute to pathological ocular neovascularization (26, 27) and to promote local adhesion of leukocytes and subsequent injury to the vascular endothelium (28, 29).

It is important to note, however, that the family of VEGF isoforms is much more than a promoter of angiogenesis as it acts in a wide variety of cellular processes (30–44) Table 2). In this regard, intravenous administration of VEGF inhibitors have been associated with an increased incidence of hypertension, proteinuria, bleeding and thromboembolic events. (45–48)

VEGF IN OCULAR NEOVASCULARIZATION

An extensive series of clinical and preclinical investigations has confirmed that VEGF plays a central role in promoting ocular neovascularization (49–56). Clinical studies have demonstrated elevated ocular levels of VEGF in patients with anterior segment neovascularization (49), retinal vein occlusion (49), neovascular glaucoma (57), retinopathy of prematurity (58), and DME (59–62). In other studies, increased expression of VEGF was detected within the maculae of patients with age-related macular degeneration (63) and in choroidal neovascular membranes (64–66)

A variety of models have been employed to demonstrate that blockage of VEGF and its receptors can inhibit the development of ocular neovascularization. In one of the first preclinical studies, Miller et al. (67) reported that experimentally induced retinal vein occlusion in monkeys resulted in iris neovascularization and an associated increase in ocular VEGF levels. Injection of anti-VEGF antibodies was shown to prevent the neovascularization of the monkey iris that normally followed laser occlusion of the vein (51), and antibodies or their Fab fragments were also effective in preventing choroidal neovascularization in a photocoagulation-induced model in monkeys (54) and in a rat corneal wound model (68). Other approaches to inactivate VEGF to prevent ocular