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.

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“…Various and heterogeneous factors, such as advanced glycation end products (AGEs), growth factors, hyperglycaemia as well as great levels of vitreous or circulating chemokines, cytokines and ROS can trigger the inflammatory responses in the retinal vasculature [94,95]. Thus, mounting evidence suggests chronic inflammation as an essential process in the development of diabetic retinopathy, primarily in early stages [96].…”

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“…DR progresses, from mild non-proliferative form, characterized by increased vascular permeability, to a moderate and severe non-proliferative phenotype, depicted by several regions of capillary closure which lead to retinal ischemia and induce upregulation of pro-inflammatory cytokines and angiogenic factors. DR can even progress to a more severe stage, the proliferative DR, characterized by the growth of new and leaky blood vessels (neovascularization) on the retina and posterior surface of the vitreous [54]. Diabetic macular edema (DME), characterized by retinal thickening resulting from blood retinal barrier breakdown, often occurring in association with altered homeostasis in Muller cells, can develop in all stages of DR and it represents the most common cause of vision loss in patients with diabetes [54,55].The pathogenesis and development of DR are highly complex due to the participation of multiple interlinked mechanisms that lead to cell injury and cellular adaptive changes in the retina [56].…”

“…DR can even progress to a more severe stage, the proliferative DR, characterized by the growth of new and leaky blood vessels (neovascularization) on the retina and posterior surface of the vitreous [54]. Diabetic macular edema (DME), characterized by retinal thickening resulting from blood retinal barrier breakdown, often occurring in association with altered homeostasis in Muller cells, can develop in all stages of DR and it represents the most common cause of vision loss in patients with diabetes [54,55].The pathogenesis and development of DR are highly complex due to the participation of multiple interlinked mechanisms that lead to cell injury and cellular adaptive changes in the retina [56]. It is increasingly evident that there are functional and structural changes in microvascular and neuroglial components, but the exact underlying mechanisms remain to be completely defined.…”

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“…On the other hand, the presence of oxidative stress and altered redox homeostasis in resident cells are characteristics commonly observed in DM patients [27][28][29]. Uncoupling endothelial nitric oxide synthase (eNOS) and the bioavailability of nitric oxide (NO) are two main factors responsible for the changes of vascular reactivity and production of reactive oxygen and nitrogen species (ROS/RNS) [30][31][32]. Additionally, dysregulation between prooxidant enzymes (e.g., NADPH oxidase complex (Nox), xanthine oxidase, cytochrome 450 and myeloperoxidase) and antioxidant enzymes (e.g., superoxide dismutase, glutathione peroxidase and catalase) is a major contributor to redox imbalance [33][34][35].…”