11 Capillary Dropout in Diabetic Retinopathy

Key Words: Diabetic retinopathy, Capillary dropout, Acellular capillaries, Endothelial cell, Apoptosis

DIABETIC RETINOPATHY

Retinopathy, one of the major microvascular complications of diabetes, is the leading cause of blindness throughout the world in the 20–74 year age group. Its effects on the quality of life and loss of productivity for patients and their families are a leading socioeconomic burden on the community. Diabetic retinopathy is a slowly progressing lifelong disease that is exacerbated by high blood pressure, puberty, or pregnancy (1, 2). It affects both type I and type II diabetic patients. With the incidence of type II diabetes increasing worldwide and the age of onset decreasing dramatically, retinopathy is becoming a major global concern.

Retinopathy is a multifactorial complication of diabetes, and sustained hyperglycemia is considered a major cause of slow and cumulative damage to the small blood vessels in the retina (3, 4). The major determinants for the progression of diabetic retinopathy are duration of diabetes and the degree of glycemic control maintained over the years (5). During the initial stages, background retinopathy, small blood vessels may begin to bleed and leak fluid into the surrounding retinal tissue, but the disease remains asymptomatic. As retinal blood vessels continue to get damaged, portions of the retinal microcirculation begin to close down causing the retina to become ischemic. Capillary dropout is a critical process in diabetic retinopathy, resulting in ischemia, release of angiogenic growth factors, and sight-threatening retinal neovascularization (6). As a result, it is necessary to gain a greater understanding of this process in order to develop improved treatments for diabetic retinopathy.

ORGANIZATION, STRUCTURE, COMPOSITION, AND FUNCTION

OF RETINAL CAPILLARIES

In order to appreciate how capillaries are damaged in the retina, it is imperative that we have a better understanding of the organization and structure of this delicate but complex tissue. The retina has four major types of cells: vascular (pericytes and endothelial cells), macroglial cells (Muller cells and astrocytes), neurons (photoreceptors, bipolar cells, amacrine and ganglion cells), and microglia (which act as phagocytes). The retinal vessels are highly organized and have three layers of microvessels: a superficial layer in the ganglion cell layer, an intermediate layer in the inner plexiform layer, and a deep layer in the outer plexiform layer (Fig. 1) (7). In humans, the retinal vessels occupy the inner half of the neural retina. The retinal vasculature is separated from the surrounding neural components by the cytoplasm of Muller cells and glial cells. Blood vessels extend outward from the optic disc in all directions spreading their network across the retina, stopping short of the periphery, and also sparing the fovea. Although the arrangement of retinal vessels is unique for each human, the larger blood vessels, in general, occupy the innermost portion of the retina while smaller blood vessels, the capillaries, are found between the nerve fiber and inner nuclear layers (8). The diameter of the capillary network varies in different parts of the retina; the outer mesh ranges from 15 to 130 m while the superficial network averages about 65 m (9). The

Fig. 1. Organization and structure of retina showing different cell types. The highly organized retinal vessels have three layers of microvessels: a superficial layer in the ganglion cell layer, an intermediate layer in the inner plexiform layer, and a deep layer in the outer plexiform layer. The retinal vasculature is separated from the surrounding neural components by the cytoplasm of Muller cells and glial cells.

Fig. 2. Retinal capillary structure showing the organization of capillary cells on the basement membrane.

retinal capillary wall is lined by a single layer of endothelial cells encompassed by a basement membrane and surrounded by pericytes (Fig. 2) (10).

The basement membrane, a connective tissue sheath, surrounds the capillaries. It is a definite membrane with a fibrillar structure and has uniform thickness. The retinal capillary basement membrane is mainly composed of collagen types IV and V, laminin and heparan sulfate proteoglycan core protein (11). Its function is to structurally support the endothelial cells and pericytes and also to anchor retinal vessels to adjacent tissues.

Fig. 3. Cross section of a capillary demonstrating tight junctions in between endothelial cells and coverage by pericytes.

The vascular endothelial cells and pericytes lie on the basement membrane (Fig. 3). Endothelial cells are the predominant cells initially but 3 months after birth, pericytes are observed on the microvessels (12). Fusion of membranes between endothelial cells forms the tight junctional complexes (7,13). These junctions are largely responsible for the blood–retinal barrier that impedes the outward passage of circulating proteins (14). The integrity of the blood–retinal barrier is essential for normal visual function, and the disruption of this barrier is seen in diabetic retinopathy and other ocular diseases. Under normal conditions, the vascular endothelium also acts as a barrier to the trafficking of leukocytes into the retina. The blood–retinal barrier serves as a selective partition between the retina and the blood circulation enabling the retina to regulate its environment in response to varying metabolic demands. In diabetes the blood–retinal barrier breaks down and permeability to larger molecules, including albumin, is increased (15).

The endothelium is surrounded by pericytes that exchange paracrine signals through a shared basement membrane (16). These cells have nuclei which often appear to protrude from the capillary wall, and have long and slender processes which envelop the wall and overlap neighboring cells (17). They are spaced regularly along the retinal capillary and are in direct contact with endothelial cells. Pericytes are not present on the newly formed capillary beds, but are seen only within the maturing vascular network (7). Pericytes provide structural support, help in contraction and regulate the endothelial cells. Contractility of pericytes confers the ability to regulate retinal vascular tone and blood flow (18).

PATHOLOGY AND CLINICAL MANIFESTATION OF CAPILLARY

DROPOUT IN DIABETIC RETINOPATHY

Capillaries function to provide nutrients (glucose, fatty acids, and amino acids) to the retina and to metabolically exchange respiratory gases, and also to remove waste products from the retina in order to maintain retinal homeostasis (19). This fundamental role of the capillaries requires proper functioning of the components of the capillaries. Capillary dropout is characterized by the loss of capillary components that results ultimately in the degeneration or obliteration of capillaries.

In the early stage or background retinopathy, the selective loss of pericytes from the retinal capillaries is consistently shown to occur before any histopathological signs can