Angiogenic Factors and Cytokines in Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is a sight-threatening complication of both type-1 and type-2 diabetes. The recent success of treatments inhibiting the function of vascular endothelial growth factor (VEGF) demonstrates that specific targeting of a growth factor responsible for vascular permeability and growth is an effective means of treating DR-associated vascular dysfunction, edema and angiogenesis. This has stimulated research of alternative therapeutic targets involved in the control of retinal vascular function. However, additional treatment options and preventative measures are still needed and these require a greater understanding of the pathological mechanisms leading to the disturbance of retinal tissue homeostasis in DR. Although severe DR can be treated as a vascular disease, abundant data suggests that inflammation is also occurring in the diabetic retina.Thus, anti-inflammatory therapies may also be useful for treatment and prevention of DR. Herein, the evidence for altered expression of angiogenic factors and cytokines in DR is reviewed and possible mechanisms by which the expression of VEGF and cytokines may be increased in the diabetic retina are examined. In addition, the potential role for microglial activation in diabetic retinal neuroinflammation is explored.

Keywords: Diabetic retinopathy; Interleukin-6; Interleukin-8; Leukocyte trafficking; Microglia; Monocyte chemoattractant protein 1; Neuroinflammation; Vascular endothelial growth factor.

Figure 1. Inflammation and vascular dysfunctions in diabetic retinopathy (DR)

In diabetic macular edema (DME), neuroinflammation with upregulated expression of cytokines such as interleukin-6 (IL-6), IL-8 (CXCL8) and monocyte chemoattractant 1 (MCP-1, CCL2), as well as intercellular adhesion molecule 1 (ICAM-1) on the luminal surface on endothelial cells leads to increased adherence of leukocytes to the luminal endothelial surface (leukostasis). This can block blood flow and damage endothelial cells. Capillary obstruction due to leukostasis and capillary dropout due to death of vascular pericytes and endothelial cells leads to tissue ischemia. Resulting hypoxia may drive expression of vascular endothelial growth factor (VEGF). VEGF promotes vascular permeability resulting in leakage of plasma through the blood-retinal barrier (BRB) and tissue edema. In proliferative diabetic retinopathy (PDR) upregulated expression of pro-angiogenic factors and down regulation of anti-angiogenic factors leads to an imbalance that causes BRB disruption and unproductive angiogenesis. Pro-angiogenic factors include VEGF, angiopoietin-2 (Ang-2), osteopontin (OPN), platelet-derived. growth factor (PDGF), erythropoietin (EPO), stomal cell derived factor (SDF-1, CXCL12) and cysteine-rich 61 (CYR61). Anti-angiogenic factors include pigment epithelium derived growth factor (PEDGF), endostatin (ES), angiostatin (AS) and tissue kallikrein (TK). Red color indicates upregulation and green indicated downregulation.