siRNA for tight junction proteins, toxins and proteins derived from microorganisms that target junction proteins, and with other molecules such as peptides, lipids, heparins, chitosan derivatives, phospholipase inhibitors, and kinase activators.5

RETINAL BLOOD FLOW AND

VASCULAR CALIBER

Retinal vascular caliber changes may reflect the cumulative structural vascular damage from multiple processes, including aging, long-term hypertension, arteriosclerosis, inflammation, endothelial dysfunction, and other vascular processes. Variations in arteriolar and venular caliber may also be influenced by physiological blood flow parameters such as oxygenation and shear stress.6

There are distinct pathophysiological factors influencing retinal arteriolar and venular caliber. The endothelial cells of arterioles and venules are molecularly distinct from the earliest stages of angiogenesis.

MECHANISMS OF RETINAL ARTERIOLAR CALIBER CHANGES

The pathophysiological changes in retinal arterioles in response to blood pressure elevation are well documented. Increased blood pressure initiates vasospasm and an increase in vasomotor tone owing to local autoregulation, leading to elevation in capillary pressure and flow. This is seen as generalized narrowing of the retinal arterioles. With persistent blood pressure elevation, chronic arteriosclerotic changes, such as intimal thickening, media wall hyperplasia, and hyaline degeneration develop. These changes manifest as diffuse arteriolar narrowing and opacification of arteriolar walls seen as “silver wiring,” and compression at the venules by arterioles at their junction as “arteriovenous nipping.” An exudative stage follows with breakdown of the BRB as a result of autoregulation failure caused by severe elevation in blood pressure. Focal or generalized dilatation of arterioles follows, along with increased permeability, necrosis of smooth muscles and endothelial cells, exudation of blood (hemorrhage) and lipids (hard exudates), and retinal ischemia. Narrowing of the arteriolar caliber is thus part of the initial stages of hypertensive retinopathy. Impairment of autoregulation in the retinal circulation has also been implicated in the pathogenesis of various retinal diseases, including diabetic retinopathy and diabetic macular edema.

The retinal blood vessels have no adrenergic vasomotor nerve supply to initiate changes in vascular tone. Furthermore, retinal blood flow has been postulated to be dependent on myogenic changes in arteriolar tone. Cultured brain endothelial cells can directly interact with smoothmuscle cells and pericytes via gap junctions, and actively regulate arteriolar tone and caliber size by elaborating vasodilators, such as nitric oxide (NO), adenosine, prostanoids, and vasoconstrictors, such as endothelin 1 and angiotensin II, in response to local metabolic needs. Among these factors, NO plays a central role in the maintenance of vascular homeostasis by regulating vascular tone and inhibiting platelet and leukocyte adhesion to endothelial cells. Recent studies have demonstrated that NO synthase may have a vasoregulatory role in the retina.7

In diabetes, endothelial dysfunction and inflammation are likely to have a major effect on the retinal microvasculature as well. Both in vitro and in vivo studies have shown that the synthesis and release of vasoconstrictors by the vascular endothelium are increased in patients with diabetes. This is consistent with the clinical observation that narrower retinal arteriolar caliber predicted the incidence of diabetes, independent of other established factors.

MECHANISMS OF RETINAL VENULAR CALIBER CHANGES

There is less understanding of the pathophysiological mechanisms of retinal venular caliber changes. Epidemiological studies have

consistently shown associations of retinal venular caliber with systemic inflammatory markers.

The association of smoking with venular dilation may involve higher carbon monoxide levels and endothelium-dependent relaxation, which may lead to a decrease in oxygen supply to retinal tissue, resulting in retinal venular dilatation. In people with diabetes and hyperglycemia, arteriolar and venular dilation may also reflect hyperperfusion resulting from hyperglycemia and lactic acidosis from retinal hypoxia.

MACULAR PIGMENTS

Three dietary carotenoids, lutein (L), zeaxanthin (Z), and mesozeaxanthin (meso-Z), accumulate at the macula, where they are collectively referred to as macular pigment. L and Z are not synthesized de novo in humans, and are entirely of dietary origin, whereas meso-Z is primarily formed in the retina from L.8

An average western diet contains 1.3–3 mg/day of L and Z combined, with significantly more L than Z (represented by an estimated ratio of 7 : 1). Approximately 78% of dietary L and Z are sourced from vegetables. L is found in highest concentrations in dark green leafy vegetables, such as spinach, kale, and collard greens. Z is the major carotenoid found in corn, orange peppers, and oranges, with a high mole percentage of both L and Z being found in egg yolk. Possible dietary sources of meso-Z include shrimp, certain marine fish and turtles, none of which is found in a typical western diet.

Macular pigment represents the most conspicuous accumulation of carotenoids in the human body. Z is the predominant carotenoid in the foveal region, whereas L predominates in the parafoveal region. The concentration of meso-Z peaks centrally.

L, Z, and meso-Z are intracellular compounds, separated between the cell cytosol and the cell membrane of the photoreceptor outersegment membranes, where they are possibly bound to the ubiquitous structural protein tubulin, or to specific xanthophyll-binding proteins. Macular pigment has been shown to reach its maximum concentration within the photoreceptor axon layer (fibers of Henle) of the foveola, whereas outside the foveola, the highest concentrations are found both within the photoreceptor axons and within the inner and outer plexiform layers.

FUNCTIONS OF MACULAR PIGMENTS

Antioxidant

Macular carotenoids are capable of quenching singlet oxygen, free radicals, and triplet-state photosensitizers, thus limiting membrane phospholipid­­ peroxidation. In vitro studies of cultured human RPE cells have demonstrated enhanced survival of these cells when they are subjected to oxidative stress in the presence of Z and other antioxidant compounds, as compared with cells subjected to the same conditions in the absence of such antioxidants.

L and Z are more resistant to degradation than other carotenoids when subjected to oxidative stress, an attribute which may facilitate their selective accumulation and slow biological turnover at the macula. Of the macular carotenoids, Z is probably a more potent antioxidant than L.

Optical filter

The absorption spectrum of the macular carotenoids peaks at 460 nm, and thus macular pigment is a filter of blue light and may limit photooxidative damage to retinal cells. Both the absorptive characteristics of macular pigment and its location in the anterior portion of individual photoreceptors enable the pigment to attenuate the amount of blue light incident upon the photoreceptor.

It has been estimated that the quantity of visible blue light (460 nm) incident upon the photoreceptors of the macula is substantially reduced

Retina in Sciences Basic • 1 section