Oxidative stress and epigenetics in ocular vascular aging: an updated review

Abstract

Vascular aging is an inevitable process with advancing age, which plays a crucial role in the pathogenesis of cardiovascular and microvascular diseases. Diabetic retinopathy (DR) and age-related macular degeneration (AMD), characterized by microvascular dysfunction, are the common causes of irreversible blindness worldwide, however there is still a lack of effective therapeutic strategies for rescuing the visual function. In order to develop novel treatments, it is essential to illuminate the pathological mechanisms underlying the vascular aging during DR and AMD progression. In this review, we have summarized the recent discoveries of the effects of oxidative stress and epigenetics on microvascular degeneration, which could provide potential therapeutic targets for DR and AMD.

Keywords: Age-related macular degeneration; Diabetic retinopathy; Epigenetics; Microvascular dysfunction; Oxidative stress; Vascular aging.

Fig. 1

Schematic illustration of retinal vascular aging in response to oxidative stress in diabetic retinopathy (DR). Oxidative stress is manifested as increased levels of ROS, NADPH oxidase and superoxide, in contrast with decreased expression of SOD, catalase and antioxidants. Oxidative stress induces endothelial degeneration, pericyte loss and basement membrane thickening, which aggravates vasoregression in the process of DR. Concurrently, retinal ischemia occurred due to the compromised endothelium-dependent dilation and decreased blood flow in retinal microvessels. Vasoregression and ischemia coordinate with each other and eventually result in BRB breakdown and neovascularization during DR progression. ROS: reactive oxygen species, SOD: superoxide dismutase

Fig. 2

The role of oxidative stress in Choroid-retinal pigment epithelium (RPE) damage during the progression of age-related macular degeneration (AMD). Oxidative stress induces ischemia and chronic inflammation in Choroid-RPE complex. Excess production of VEGF in response to ischemia initiates pathological angiogenesis, and then choroidal neovascularization (CNV) develops as a consequence. In addition, oxidative stress contributes to overactivation of inflammatory responses, consisted of the accumulation of membrane attack complex (MAC) and senescence-associated secretory phenotype (SASP), as well as the recruitment of activated macrophages and microglia

Fig. 3

Diagram of the epigenetic regulation of vascular aging in DR and AMD. The dysregulation of DNA methylation, histone modifications and microRNA in microvessels induces alterations in the expression of targeted genes, which are responsible for vascular aging in the process of DR and AMD. AMD: age-related macular degeneration, CXCR4: C-X-C chemokine receptor type 4, DLL4: Delta like ligand 4, DNMT: DNA methyltransferase, DR: diabetic retinopathy, ET1: endothelin-1, FZD4: frizzled-4, GSTM1: glutathione S-transferase isoform mu1, HAT: histone acetyltransferase, HDAC: histone deacetylase, HIF-2α: hypoxia inducible factor 2α, HMT: histone methyltransferase, KEAP1: Kelch-like ECH-associated protein 1, LIMK2: LIM domain-containing kinase 2, MMP9: matrix metalloproteinase 9, mtDNA: mitochondrial DNA, PAK4: P21-activated kinase 4, PRSS50: protease serine 50, SEMA6A: semaphorin6A, SIRT1: sirtuin 1, SOD2: superoxide dismutase 2, SPRY2: sprouty RTK signaling antagonist 2, VEGF: vascular endothelial growth factor