Angiogenic and Antiangiogenic Factors in Proliferative Diabetic Retinopathy

Abstract

Diabetic retinopathy continues to be the leading cause of legal blindness among working-age individuals. The earliest histological features of diabetic retinopathy include neuroretinal damage, capillary basement membrane thickening, loss of pericytes and loss of endothelial cells. At advanced stages, neovascularization, the hallmark of proliferative diabetic retinopathy (PDR) occurs, and blindness can result from relentless abnormal fibrovascular proliferation with subsequent bleeding and retinal detachment. Macular oedema is another retinal complication of diabetes that is responsible for a major part of vision loss, particularly in type 2 diabetes. The breakdown of the blood retinal barrier and the consequent vascular leakage and thickening of retina are the main events involved in its pathogenesis. Although a tight control of both blood glucose levels and hypertension are essential to prevent or arrest progression of the disease, the recommended goals are difficult to achieve in many patients. Laser photocoagulation treatment soon after the onset of PDR significantly reduces the incidence of severe vision loss. However, the optimal timing for laser treatment is frequently passed and, in addition, it is not uniformly successful in halting visual decline. For all these reasons, new pharmacological treatments based on the understanding of the pathophysiological mechanisms of diabetic retinopathy have been developed in recent years. There is mounting evidence to suggest that angiogenic factors play a crucial role in PDR development, vascular endothelial growth factor (VEGF) being the most relevant. Other growth factors or cytokines such as insulin-like growth factor I (IGF-1), hepatocyte growth factor (HGF), basic fibroblast growth factor (b-FGF), platelet derived growth factor (PDGF), pro-inflammatory cytokines and angiopoetins, are also involved in the pathogenesis of PDR. However, the intraocular synthesis of angiogenic factors is counterbalanced by the synthesis of antiangiogenic factors. Therefore, the balance between the angiogenic and antiangiogenic factors rather than angiogenic factors themselves will be crucial in determining the progression of PDR. The main antiangiogenic factor is the pigment epithelium derived factor (PEDF) but the transforming growth factor beta (TGF-beta), thrombospondin (TSP) and somatostatin are also among the intraocullary synthesized antiangiogenic factors.

The PKCβ/HuR/VEGF pathway in diabetic retinopathy

“…Within this context, the few clinical trials performed with the PKCβ inhibitor ruboxistaurin (LY333531) show that this inhibitor, even though moderately reduces the incidence of visual loss, seems not to affect the progression of proliferative diabetic retinopathy [45]. This observation suggests the possible implication in the latter of VEGF-and PKC-14 independent mechanisms [46,47]. On the other hand, VEGF mRNA bears a characteristic motif found in its 3'-untranslated region, called Adenine uridine-Rich Element (ARE), which generally governs the decay rates of specific mRNAs and represents the docking site for some RBPs [48].…”

Angiogenesis and tumour progression: migration-stimulating factor as a novel target for clinical intervention

“…[1][2][3] The induction of an analogous angiogenic response is also fundamental to the aetiology of other general and ophthalmic pathologies, including fibrosis, rheumatoid arthritis, proliferative diabetic retinopathy, and age-related macular degeneration. [4][5][6] The important contribution of vascular endothelial growth factor (VEGF) to the initiation of angiogenesis in these conditions is now well established, with beneficial outcomes of VEGF-targeted therapy beginning to be achieved in certain conditions. 7,8 In spite of these encouraging results, it remains apparent that further basic and translational research is required for antiangiogenic therapy to realise its full clinical potential for patients with cancer 9-11 and for neovascular-driven ophthalmic pathologies.…”

Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1β by suppressing AMP-activated protein kinase (AMPK) activation

“…Because of the high prevalence of type 2 diabetes, DMO is the main cause of visual impairment for diabetic patients [2]. Vascular leakage caused by the breakdown of the blood-retinal barrier (BRB) is the main event involved in the pathogenesis of DMO [3,4]. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study on DR, treatment with fenofibrate (a peroxisome proliferatoractivated receptor [PPAR]-α agonist) reduced the need for laser treatment for DMO and PDR by 30% [5].…”