Abstract
Integrins are a class of transmembrane receptors that are involved in a wide range of biological functions. Dysregulation of integrins has been implicated in many pathological processes and consequently, they are attractive therapeutic targets. In the ophthalmology arena, there is extensive evidence suggesting that integrins play an important role in diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma, dry eye disease and retinal vein occlusion. For example, there is extensive evidence that arginyl-glycyl-aspartic acid (Arg-Gly-Asp; RGD)-binding integrins are involved in key disease hallmarks of DR and neovascular AMD (nvAMD), specifically inflammation, vascular leakage, angiogenesis and fibrosis. Based on such evidence, drugs that engage integrin-linked pathways have received attention for their potential to block all these vision-threatening pathways. This review focuses on the pathophysiological role that RGD-binding integrins can have in complex multifactorial retinal disorders like DR, diabetic macular edema (DME) and nvAMD, which are leading causes of blindness in developed countries. Special emphasis will be given on how RGD-binding integrins can modulate the intricate molecular pathways and regulate the underlying pathological mechanisms. For instance, the interplay between integrins and key molecular players such as growth factors, cytokines and enzymes will be summarized. In addition, recent clinical advances linked to targeting RGD-binding integrins in the context of DME and nvAMD will be discussed alongside future potential for limiting progression of these diseases.
Highlights
Integrin receptors are transmembrane heterodimeric adhesion pro teins that play an essential role in integrating the extracellular to the intracellular environment
This review focuses on the pathophysiological role that RGD-binding integrins can have in complex multi factorial retinal disorders like diabetic retinopathy (DR), diabetic macular edema (DME) and neovascular AMD (nvAMD), which are leading causes of blindness in developed countries
A vast number of articles on integrins have been published on a regular basis and it is established that these receptors are involved in various cellular processes such as adhesion, differentiation, shape, migration, signalling, invasion, prolif eration and survival with clear linkage to pathological processes, including inflammation, vascular leakage, neovascularization and fibrosis (Eklund et al, 2017; Fu et al, 2007; Hammes et al, 1996; Kanda et al, 2012; Koch and Distler, 2007; Santulli et al, 2008; Umeda et al, 2006; Wilkinson-Berka et al, 2006; Zahn et al, 2009)
Summary
Integrin receptors are transmembrane heterodimeric adhesion pro teins that play an essential role in integrating the extracellular to the intracellular environment. In the last few years, there has been renewed interest in integrins and especially drugs that target arginyl-glycyl-aspartic acid (Arg-Gly-Asp; RGD) -binding integrins in tissues of the eye. This reinvigoration in the area has been driven, at least in part, by recent preclinical and clinical studies which demonstrated promising results in retinal diseases such as diabetic retinopathy (DR), diabetic macular edema (DME) and neo vascular age-related macular degeneration (nvAMD) (Askew et al, 2018; Shaw et al, 2020; Tolentino et al, 2016). We will endeavour to provide compre hensive information on the intricate cellular and molecular mechanisms of RGD-binding integrin signalling in the main disease hallmarks of these vision-threatening retinal disorders
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