Implications of fibrotic extracellular matrix in diabetic retinopathy

Abstract

Fibrosis is an accumulation of extracellular matrix (ECM) proteins and fibers in a disordered fashion, which compromises cell and tissue functions. High glucose-induced fibrosis, a major pathophysiological change of diabetic retinopathy (DR), severely affects vision by compromising the retinal vasculature and ultimately disrupting retinal tissue organization. The retina is a highly vascularized, stratified tissue with multiple cell types organized into distinct layers. Chronically high blood glucose stimulates certain retinal cells to increase production and assembly of ECM proteins resulting in excess ECM deposition primarily in the capillary walls on the basal side of the endothelium. This subendothelial fibrosis of the capillaries is the earliest histological change in the diabetic retina and has been linked to the vascular dysfunction that underlies DR. Proteins that are not normally abundant in the capillary basement membrane (BM) matrix, such as the ECM protein fibronectin, are assembled in significant quantities, disrupting the architecture of the BM and altering its properties. Cell culture models have identified multiple mechanisms through which elevated glucose can stimulate fibronectin matrix assembly, including intracellular signaling pathways, alternative splicing, and non-enzymatic glycation of the ECM. The fibrotic subendothelial matrix alters cell adhesion and supports further accumulation of other ECM proteins leading to disruption of endothelial cell-cell junctions. We review evidence supporting the notion that these molecular changes in the ECM contribute to the pathogenesis of DR, including vascular leakage, loss of endothelial cells and pericytes, changes in blood flow, and neovascularization. We propose that the accumulation of ECM, especially fibronectin matrix, first around the vasculature and later in extravascular locations, plays a critical role in DR and vision loss. Strategies for DR prevention and treatment should consider the ECM a potential therapeutic target.

Keywords: Diabetic retinopathy; basement membrane; extracellular matrix; fibronectin; fibrosis; neovascularization.

Figure 1.

(A) The cartoon depicts the layers of the retina including the capillary networks. Light passes through the vitreous and inner (IR) and outer retinal (OR) layers as indicated on the left. The OR contains photoreceptor cells that respond to light. The IR contains interneurons that transduce signals to neurons that project axons from the IR to the brain. Specialized ECMs (green) called the inner limiting membrane (ILM, top) and Bruch’s membrane (bottom) separate the IR from the vitreous and the retinal pigmented epithelium in the OR from the choroid, respectively. Blood vessels feeding the layers are shown on the right. The OR is nourished by diffusion from the choroidal vasculature, while the IR contains a capillary network that extends throughout the layers, branching from arteries and veins shown under the ILM. (B) Cross-section of normal (left) and fibrotic (right) retinal capillaries. In normal conditions, the capillary wall is composed of a monolayer of endothelial cells (red) on a thin laminar basement membrane (gray). In conditions of chronically high blood glucose, the basement membrane becomes fibrotic and thickens as much as 20-fold (green). Pericytes wrap around the capillary wall (tan cells). Red disks inside the capillary represent the red blood cells. (A color version of this figure is available in the online journal.) Source: Adapted from Gameiro et al. (http://creativecommons.org/licenses/by/4.0/).

Figure 2.

The relationship between high glucose, ECM, fibrosis, and pathology in DR is outlined in this flowchart (see text for details).