This was described by Cunha-Vaz and colleagues [2–4]. It is primarily due to complex tight cell junctions (zonulae occludentes) of retinal capillary endothelial cells. Retinal astrocytes, Müller cells, and pericytes also contribute to the proper functioning of the inner BRB [5], and they may influence tight cell junction formation and maturation [6]. Let us look at the role of the various components of the inner BRB:

In summary, the tight junction of endothelial cells in the inner BRB could be developed by cellular interactions between Müller cells, pericytes, astrocytes, and endothelial cells [32].

There is evidence that angiopoietin 2 may play a role in the regulation of BRB [33, 34].

The inner BRB is compromised in several conditions, including diabetes mellitus, retinal vein occlusion, and various inflammatory diseases.

The outer BRB is located in the RPE, which is a single cell layer and separates the outer surface of the retina from the choriocapillaris (Fig. 9.1). The outer retina is supplied by the choriocapillaris. The RPE has three important functions. (1) Because of the presence of the BRB in the RPE, it regulates the entry of nutrients from the blood in the choriocapillaris to the photoreceptors; (2) it removes waste products; and (3) it maintains its adhesion with the retina. Choriocapillaris have fenestrations, so that they leak profusely, allowing passage of large molecules such as albumin into the extravascular spaces of the choroid. The tight cell junctions of the RPE, which constitutes the outer BRB, prevent diffusion of fluid from the choroid into the retina. Initially during development, RPE cell junctions are leaky, and later on, they develop tight cell junctions [43]. GTPase Rap1 regulates the formation and maintenance of the RPE cell junctional barrier; it is an important regulator of RPE cell junctions and is required for maintenance of barrier function [44].

Oxidized low-density lipoprotein could promote senescence of RPE cells, which leads to outer BRB dysfunction as an early pathogenesis of age-related macular degeneration [45]. In hypertensive choroidopathy, because of ischemia of the RPE, there is breakdown of the outer BRB resulting in serous retinal detachment [46]. Breakdown of the outer BRB has also been reported in diabetes and ischemia [47].

For transport across the RPE, these cells show marked apico-basal polarity, with long apical microvilli and deep basal infoldings [48]. Nutrients and vitamin A are transported in baso-apical direction from the blood to the photoreceptors. Removal of metabolites, extracellular fluid, and ions takes place by transcellular transport from the subretinal space toward the choriocapillaris bed.

It is the protein complex at the tight cell junction that allows the establishment of the polarities of the BRB, restricting paracellular diffusion of blood barrier compounds into the neuronal tissues [3, 49]. Creation of cell polarity is a distinguishing feature of a tissue barrier. This cell polarity is associated with organization of the cytoskeleton, apical/basal cell membrane proteins, and organization of the junctional complexes between neighboring cells [50]. The ability of RPE to regulate transport through it depends upon two properties: (1) presence of tight cell junctions to prevent diffusion through the spaces in between the cells and (2) an asymmetric distribution of proteins to regulate vectorial transport across the monolayer [43].

There is no barrier within the retinal tissue itself [46], so there is a constant movement of small molecules (mainly water) from the vitreous cavity into the inner retina and through the RPE to the choroid. The internal limiting membrane prevents diffusion of macromolecules but allows the passage of smaller molecules.

The retina is a transparent structure, and that is essential for its normal optical visual function, for the light to go uninterrupted to the photoreceptors. For proper physiological integrity of the retinal vessels, microenvironment, homeostasis, and visual function of the retina, an efficient BRB is essential. The tight interendothelial cell junctions block movement of macromolecules toward the retinal interstitial space. A collection of fluid in the retina not only causes edema but also may interfere with its transparency.

The transport of nutrients to the retina and removal of waste products from it through the BRB occurs in two ways: (1) transcellular and (2) paracellular. By the transcellular pathway, most proteins are transported nonselectively within vesicles, either in their fluid phase or adsorbed to the vesicular membrane [51]. Constitutive transcytosis of albumin across the vascular endothelium is done by adsorption or as bulk fluid and is implicated in regulating the transvascular oncotic pressure gradient of albumin [52, 53]. By the paracellular pathway, generally water, ions, and small non-charged solutes are transported by passive diffusion and with low selectivity along electrochemical and osmotic gradients that are built up by the activity of transcellular transporters or by external gradients of solutes [54].

The outer retinal layers, including the photoreceptors, and peripheral retina are avascular. They are supplied by the choroidal vascular bed. RPE regulates entry of nutrients from the blood in the choriocapillaris to the photoreceptors and also eliminates waste products. Tight cell junctions between the RPE cells prevent leakage of fluid from the choroid to the retina, helping to maintain RPE adhesion with the retina. This barrier breaks down when the RPE cells are destroyed or subjected to ischemia, as in hypertensive choroidopathy (Fig. 9.2) [46].

Cunha-Vaz [55] described the transport of major electrolytes in the BRB, with a net K⁺ flux from retina to blood and a net Mg⁺⁺ flux in the opposite direction across the BRB sites, and that provides a low K⁺ and high Mg⁺⁺ extracellular environment in the retina. There is also absorptive transport of amino acids across the endothelial and chorioretinal components of the BRB, and that creates a continuous “flow” of these important precursors into the retina. Active absorptive transport across the blood-ocular barrier system removes several substances, including organic anions from the extracellular fluid of the retina. He stated that both the outer and inner components of the BRB have a variety of absorptive transport processes, which are capable of removing potentially harmful substances from the extracellular fluid of the retina.

Studies have shown that corticosteroids, such as intravitreal triamcinolone acetonide, inhibit breakdown of the BRB.

A fluorescein angiography study showed that acetazolamide increased unidirectional passive permeability by stimulation of the outward active transport of ion and fluid from the retina to the choroid [61, 62], and the edema-reducing effect of acetazolamide is due to decreased leakage and stimulated active transport across the BRB [41].