Sweet Stress: Coping With Vascular Dysfunction in Diabetic Retinopathy

Abstract

Oxidative stress plays key roles in the pathogenesis of retinal diseases, such as diabetic retinopathy. Reactive oxygen species (ROS) are increased in the retina in diabetes and the antioxidant defense system is also compromised. Increased ROS stimulate the release of pro-inflammatory cytokines, promoting a chronic low-grade inflammation involving various signaling pathways. An excessive production of ROS can lead to retinal endothelial cell injury, increased microvascular permeability, and recruitment of inflammatory cells at the site of inflammation. Recent studies have started unraveling the complex crosstalk between retinal endothelial cells and neuroglial cells or leukocytes, via both cell-to-cell contact and secretion of cytokines. This crosstalk is essential for the maintenance of the integrity of retinal vascular structure. Under diabetic conditions, an aberrant interaction between endothelial cells and other resident cells of the retina or invading inflammatory cells takes place in the retina. Impairment in the secretion and flow of molecular signals between different cells can compromise the retinal vascular architecture and trigger angiogenesis. In this review, the synergistic contributions of redox-inflammatory processes for endothelial dysfunction in diabetic retinopathy will be examined, with particular attention paid to endothelial cell communication with other retinal cells.

Keywords: apoptosis; blood–retinal barrier; diabetic retinopathy; inflammation; neovascularization; oxidative stress; retinal endothelial cells.

FIGURE 1

Schematic cross-section showing the retinal blood vessels lining the inner surface of the retina. Three capillary plexuses are embedded among retinal neurons: the superficial layer lies within the inner nerve fiber layer (NFL) with branches extending into the ganglion cell layer (GCL), while the intermediate and deep capillary plexuses align along each sides of the inner nuclear layer (INL). ONL, outer nuclear layer. IPL, inner nuclear layer; OPL, outer plexiform layer.

FIGURE 2

Biochemical pathways leading to diabetic retinopathy. Chronic hyperglycemia promotes the increase in ROS formation, originating in the mitochondria or produced by Nox, and also activates many metabolic pathways, including PKC, polyol pathway, AGEs, and the hexosamine pathway, as well as the production of inflammatory mediators. Oxidative stress damages mitochondrial DNA resulting in a decline in mitochondrial function, which accelerates cell apoptosis, contributing to the development of diabetic retinopathy.

FIGURE 3

Processes leading to BRB breakdown in diabetic retinopathy. During the development of diabetic retinopathy, increased production of ROS leads to increased expression of intercellular adhesion molecules in endothelial cells, and consequently increased leukocyte adhesion. Concurrently, astrocytes, Müller cells, and microglia become activated, promoting cytokine release, and pericytes surrounding endothelial cells die by apoptosis. Moreover, vascular ROS and inflammatory mediators that are released by inflammatory cells affect endothelial tight junctions leading to increased BRB permeability.