Blood Retinal Barrier

Fully developed retina is organized into the following layers (Fig. 9): retinal pigment epithelium (RPE), photoreceptor layer, outer limiting membrane, outer nuclear layer, outer plexiform layer, inner nuclear layer, inner plexi-form layer, ganglion cell layer, nerve fiber layer, and inner limiting membrane (Wu, 1995). Large retinal vessels are present in the optic nerve fiber layer, and retinal capillaries are present between the inner nuclear layer and the outer plexiform layer. The outer and inner limiting membranes of the retina are quite permeable. The outer limiting membrane has traditionally been described as a layer of zonulae adherens that connect Muller cells to photoreceptors, and it is permeable to macromolecules. The inner limiting membrane is a continuous glycoprotein coating identical to the basal lamina of epithelia or endothelia. The inner limiting membrane contains the cell bodies of most neurons and forms a basement membrane for the Muller and glial cells and separates the base of the Muller cells from the vitreous body. The intercellular clefts between the Muller cell processes that abut the inner limiting membrane are open and lack specialized intercellular junctions. Freeze-fracture studies confirmed the absence of zonulae occludens between the basal feet of the Muller cells in both humans and monkey. The perme-

Figure 9 Cellular organization of the retina.

ability properties of inner limiting membrane are likely similar to the basal laminae, which retain particulate matter but allow the transport of molecules up to the size of ferritin (400 kDa) (Wu, 1995). Among all the retinal layers, the principal barrier to solute transport is the blood-retinal barrier (BRB), which includes retinal pigment epithelium and retinal vessels.

The BRB is located at two levels: the outer BRB, consisting of the retinal pigment epithelium (RPE), and the inner BRB, consisting of the endothelial membranes of the blood vessels of the retina. BRB plays a critical role in the homeostatis of the neural retina by limiting the entry of xenobiotics into the extravascular spaces of the retina and by preventing the loss of essential solutes. Blood-retinal barrier breakdown, a key factor underlying pathological conditions such as diabetic retinopathy, is a leading cause of vision loss. In neovascular disorders such as proliferative diabetic retinopathy or age-related choroidal neovascularization, elevation of angiogenic factors such as vascular endothelial growth factor (VEGF165) and transforming growth factor (TGF-y8), can disrupt the blood-retinal barrier (Behzadian et al., 2001). Quantification of the degree of damage to blood-retinal barrier can be performed by locating 125I- and 135I-albumin tracers (Miyamoto et al., 1999) or Evans blue in the retinal tissue and/or vitreous following their systemic injection (Xu et al., 2001).

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