Molecular and Cellular Mechanisms Involved in the Pathophysiology of Retinal Vascular Disease-Interplay Between Inflammation and Oxidative Stress

Abstract

Retinal vascular diseases encompass several retinal disorders, including diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and retinal vascular occlusion; these disorders are classified as similar groups of disorders due to impaired retinal vascularization. The aim of this review is to address the main signaling pathways involved in the pathogenesis of retinal vascular diseases and to identify crucial molecules and the importance of their interactions. Vascular endothelial growth factor (VEGF) is recognized as a crucial and central molecule in abnormal neovascularization and a key phenomenon in retinal vascular occlusion; thus, anti-VEGF therapy is now the most successful form of treatment for these disorders. Interaction between angiopoietin 2 and the Tie2 receptor results in aberrant Tie2 signaling, resulting in loss of pericytes, neovascularization, and inflammation. Notch signaling and hypoxia-inducible factors in ischemic conditions induce pathological neovascularization and disruption of the blood-retina barrier. An increase in the pro-inflammatory cytokines-TNF-α, IL-1β, and IL-6-and activation of microglia create a persistent inflammatory milieu that promotes breakage of the blood-retinal barrier and neovascularization. Toll-like receptor signaling and nuclear factor-kappa B are important factors in the dysregulation of the immune response in retinal vascular diseases. Increased production of reactive oxygen species and oxidative damage follow inflammation and together create a vicious cycle because each factor amplifies the other. Understanding the complex interplay among various signaling pathways, signaling cascades, and molecules enables the development of new and more successful therapeutic options.

Keywords: angiogenesis; cellular signaling; retinal vascular diseases; vascular endothelial growth factor.

Figure 1

Representation of the physiological structure of the retina and retinal vascularization.

Figure 2

Pathological hallmarks of non-proliferative (NPDR) and proliferative (PDR) stages of DR, including aneurysms, hemorrhages, hard exudates, cotton wool spots in NPDR, and abnormal neovascularization and macular edema, combined with previous for PDR.

Figure 3

Retinopathy of prematurity (ROP)—different phases of ROP including impaired retinal vascular development in utero induced by low VEGF values, and pathological changes followed by increased VEGF production such as abnormal neovascularization, excessive fibrous tissue growth, and retinal detachment. Anti-VEGF therapy, applied at an early stage as prevention, or when the disease appears, can lead to resolution.

Figure 4

Age-related macular degeneration—the main pathological hallmark of the dry form of AMD is drusen formation, while patients in the wet form of the disease have exudation and hemorrhages as crucial characteristics.

Figure 5

Retinal vascular occlusions—the main etiological factors involved in the pathogenesis of retinal vascular occlusions and clinical presentation of retinal artery and retinal vein occlusion.

Figure 6

Carotid artery stenosis and ocular implications. Various risk factors contribute to the development of carotid artery stenosis with the consequent development of different aspects of ocular ischemic syndrome and chronic ocular ischemic disease.

Figure 7

Molecular and cellular signaling in the pathogenesis of ischemic retinal diseases—the key role of VEGF. Abbreviations: Ang2, angiopoietin 2; EPO, erythropoietin; HIF-1α, hypoxia-inducible factor-1α; PDGF, platelet-derived growth factor; AGEs, advanced glycation end products; IGF-1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; Jag1,2, Jagged 1 and 2; Dll1,3,4, Delta-like ligands 1, 3 and 4; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; PKB, protein kinase B; NOS, nitric oxide synthase; BRB, blood–retina barrier.

Figure 8

Inflammatory pathways in retinal vascular disorders—the interplay between different interleukins, chemokines, microglia, and development of neovascularization and vascular retinal diseases. Abbreviations: IL-1β, interleukin 1β; IL-6, interleukin 6; IL-10, interleukin 10; TNF-α, tumor necrosis factor α; MCP-1, monocyte chemoattractant protein 1; CCL2, CC motif chemokine ligand 2; CCL5, CC motif chemokine ligand 5; CXCL10, CXC motif chemokine ligand 10; DAMPs, damage-associated molecular pattern molecules; TLR4, toll like receptor 4; NF-κB, nuclear factor-kappa B; BRB, blood–retina barrier.

Figure 9

Oxidative stress and damage of retinal cells. Abbreviations: Nox/Duox, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/dual oxidase; NOS, nitric oxide synthase; eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; iNOS, inducible nitric oxide synthase; ^•HO, hydroxyl radical; ^•O₂², peroxide ion radical; ^•O₂, superoxide anion radical; ^•ONOO, peroxynitrite; ^•NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species.

Figure 10

The relation of reactive species and oxidative stress in the development of diabetic retinopathy and age-related macular degeneration. Abbreviations: AGE/RAGE, advanced glycation end products/receptors; GSH, reduced glutathione; IL-1β, interleukin 1β; iNOS, inducible nitric oxide synthase; MDA, malondialdehyde; NF-κB, nuclear factor-kappa B; NO, nitric oxide; Nox, NADPH oxidase system; PKC, protein kinase C; TNF-α, tumor necrosis factor α.