INTRODUCTION

Diabetic retinopathy is the most prevalent cause of vision loss among adults of working age, and diabetic macular edema (DME) is the most common cause of moderate vision loss in individuals with diabetes mellitus (1), especially in patients with type 2 diabetes (2). Diabetic retinopathy accounts for an estimated 15–17% of the 2.7 million cases of blindness in the European Union (3). In the United States, an estimated 4.1 million individuals aged 40 years and older are affected by diabetic retinopathy, with nearly 900,000 having vision-threatening disease (4).

There are two major causes that lead to deterioration of vision in diabetic retinopathy:

(1) direct damage to the retinal vasculature and (2) development of retinal neovascularization. Severe visual loss in patients with diabetes occurs primarily as a consequence of retinal neovascularization and complications resulting from intraocular angiogenesis such as vitreous hemorrhage or tractional retinal detachment; moderate visual loss results primarily from DME related to altered permeability of the retinal vasculature.

Currently, laser photocoagulation is the standard of care in treating retinal complication s of diabetes, and while it has contributed significantly to reducing the incidence of severe vision loss, it is basically a destructive intervention that does not address the underlying pathophysiology. The mechanism by which scatter laser photocoagulation reduces proliferative retinopathy is not known. It has been proposed that light energy absorbed by melanin in the retinal pigment epithelium destroys highly metabolically active outer retinal cells, reducing retinal oxygen consumption and facilitating improved oxygen diffusion from the choriocapillaris through the laser scars (5). By destroying a portion of viable retina, laser therapy also lessens the metabolic load and therefore the absolute need for oxygen.

However, laser treatment is accompanied by frank destruction of neural tissue and can lead to night blindness, visual field constriction, and dyschromatopsia. A progression in the severity of retinopathy after treatment is not uncommon (2). There is thus a need for newer therapies with fewer side effects, especially approaches that counter retinopathic change through targeting the underlying pathophysiology of DR, rather than relying on ex post facto ablation.

Metabolic control, intraocular steroids, and novel pharmacological therapy such as vascular endothelial growth (VEGF) factor blockers may help to decrease DME and may reverse vision loss associated with this disease. This chapter reviews the pathogenesis of DME, the rationale for the role of anti-VEGF agents, and preliminary clinical studies on the use of ranibizumab (Lucentis™, Genentech Inc., South San Francisco, CA) and pegaptanib (Macugen, OSI/Eyetech, New York, NY) for DME.

Pathogenesis

DME occurs from leakage of plasma into the central retina, resulting in thickening of the retina because of excess interstitial fluid. The excess interstitial fluid within the macula results in stretching and distortion of photoreceptors which eventually leads to decreased vision. Histopathological studies have demonstrated that microaneurysms are likely to be responsible for focal leakage that may be seen in eyes with DME. Microaneurysms are thought to form because of hyperglycemia-induced pericyte death, which weakens the walls of retinal vessels resulting in the formation of small aneurysms which lose

their barrier qualities and leak (6). In addition to focal leakage caused by microaneurysms, eyes with DME may also demonstrate diffuse leakage from retinal capillaries that do not show visible structural changes such as microaneurysms. This pattern of diffuse leakage may be due to microscopic damage to retinal vessels that is not visible in images obtained during fluorescein angiography. It is possible that diffuse leakage results from the presence of excessive amounts of permeability factors.

VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)

Retinal hypoxia has been implicated in the pathogenesis of DME (7). Hypoxia causes increased expression of VEGF, a potent inducer of vascular permeability that has been shown to cause leakage from retinal vessels (8, 9). VEGF was isolated independently by two groups, first as a vascular permeability factor (10) and second as a potent endothelial cell mitogen (11).

The VEGF family, which includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor, plays an important role in angiogenesis and vascular permeability (10–12), among other things. Studies have demonstrated that VEGF-A is a primary activator of angiogenesis and vascular permeability, whereas other VEGF family members play a lesser role in angiogenesis. Nine VEGF-A isoforms are produced through alternate splicing of the mRNA of the human VEGF-A gene:

VEGF121, VEGF145, VEGF148, VEGF162, VEGF165, VEGF165b, VEGF183, VEGF189, and VEGF206. (13). Among the nine isoforms, VEGF165 is the most abundantly expressed

VEGF-A isoform, and it plays a critical role in angiogenesis. However, other isoforms, such as VEGF121, VEGF183, and VEGF189, are also commonly expressed in various tissues (14). Although investigations during the 1980s suggested numerous proangiogenic and antiangiogenic factors, only VEGF convincingly showed all the characteristics of a necessary and sufficient inducer of angiogenesis (15).

VEGF IN PHYSIOLOGICAL AND PATHOLOGICAL ANGIOGENESIS

Over the past 15 years, an extensive body of research has established that VEGF is a key regulator of both physiological and pathological angiogenesis, playing a variety of roles in promoting blood vessel growth and vascular permeability (Table 1). Alternative splicing of the human gene yields at least 6 biologically active isoforms; each composed of 121, 145, 165, 183, 189, and 206 amino acids (15).

Table 1

Actions of VEGF in Promoting Angiogenesis

Endothelial cell mitogen

•Endothelial cell survival factor

•Chemoattractant for bone marrow-derived endothelial cells

•Chemoattractant for monocyte lineage cells

•Inducer of synthesis of endothelial nitric oxide synthase, and consequent elevation of nitric oxide, itself a promoter of angiogenesis

•Inducer of synthesis of enzymes promoting blood vessel extravasation

–Matrix metalloproteinases

–Plasminogen activator