The expanding role of vascular endothelial growth factor inhibitors in ophthalmology

Abstract

Vascular endothelial growth factor (VEGF) plays an important role in both physiologic and pathologic angiogenesis and contributes to increased permeability across both the blood-retinal and blood-brain barriers. After 2 decades of extensive research into the VEGF families and receptors, specific molecules have been targeted for drug development, and several medications have received US Food and Drug Administration approval. Bevacizumab, a full-length antibody against VEGF approved for the intravenous treatment of advanced carcinomas, has been used extensively in ophthalmology for exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusions, retinopathy of prematurity, and other chorioretinal vascular disorders. Pegaptanib and ranibizumab have been developed specifically for intraocular use, whereas the soon-to-be-introduced aflibercept (VEGF Trap-Eye) is moving through clinical trials for both intraocular and systemic use. Although these drugs exhibit excellent safety profiles, ocular and systemic complications, particularly thromboembolic events, remain a concern in patients receiving therapy. Patients experiencing adverse events that may be related to VEGF suppression should be carefully evaluated by both the ophthalmologist and the medical physician to reassess the need for intraocular therapy and explore the feasibility of changing medications. For this review a search of PubMed from January 1, 1985 through April 15, 2011, was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, diabetic retinopathy, retina vein occlusions, retinopathy of prematurity, intravitreal injections, bevacizumab, ranibizumab, and VEGF Trap. Studies were limited to those published in English. Other articles were identified from bibliographies of retrieved articles and archives of the author.

FIGURE 1

Under conditions of normal oxygen tension (left), HIF-1α undergoes hydroxylation, binds to the VHF, and undergoes degradation within proteosomes. When tissues experience localized hypoxia or inflammation (right), HIF-1α stabilizes and binds to the promoter site of the VEGF gene, thereby increasing VEGF synthesis. EGF = epidermal growth factor; FGF = fibroblast growth factor; HIF-1α = hypoxia-inducible factor-1α; IGF-1 = insulin-like growth factor 1; IL = interleukin; KGF = keratinocyte growth factor; O₂ = oxygen; PDGF = platelet-derived growth factor; PKC-β = protein kinase C-β; TGF = transforming growth factor; VEGF = vascular endothelial growth factor; VHF = von Hippel-Lindau factor.

FIGURE 2

The primary site of VEGF action is vascular endothelium. In response to VEGF, endothelial cells proliferate and migrate; locally release nitric oxide, which causes vasodilation; and increase capillary permeability by creating cellular fenestrations and decreasing the integrity of tight junctions by phosphorylating intracellular and extracellular proteins. ICAM-1 = intercellular adhesion molecule 1; No = nitric oxide; Pl = phosphatidylinositol; VEGF = vascular endothelial growth factor; VEGFR-2 = vascular endothelial growth factor receptor 2; ZO = zonula occludins.

FIGURE 3

The most common indications for intraocular anti-VEGF injections include exudative age-related macular degeneration, background and proliferative diabetic retinopathy, branch and central (shown in diagram) retinal vein occlusions, and retinopathy of prematurity. Intraocular anti-VEGF drugs generally work through 2 mechanisms: decreasing vascular permeability, thereby allowing the absorption of edema, and decreasing neovascularization, thereby preventing hemorrhages and tissue distortion by fibrous proliferation. RPE = retinal pigment epithelium; VEGF = vascular endothelial growth factor.

FIGURE 4

Possible systemic complications of anti-VEGF drug therapy. VEGF = vascular endothelial growth factor.