Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is a common complication of diabetes and constitutes a major cause of vision impairment and blindness in the world. DR has long been described exclusively as a microvascular disease of the eye. However, in recent years, a growing interest has been focused on the contribution of neuroretinal degeneration to the pathogenesis of the disease, and there are observations suggesting that neuronal death in the early phases of DR may favor the development of microvascular abnormalities, followed by the full manifestation of the disease. However, the mediators that are involved in the crosslink between neurodegeneration and vascular changes have not yet been identified. According to our hypothesis, vascular endothelial growth factor (VEGF) could probably be the most important connecting link between the death of retinal neurons and the occurrence of microvascular lesions. Indeed, VEGF is known to play important neuroprotective actions; therefore, in the early phases of DR, it may be released in response to neuronal suffering, and it would act as a double-edged weapon inducing both neuroprotective and vasoactive effects. If this hypothesis is correct, then any retinal stress causing neuronal damage should be accompanied by VEGF upregulation and by vascular changes. Similarly, any compound with neuroprotective properties should also induce VEGF downregulation and amelioration of the vascular lesions. In this review, we searched for a correlation between neurodegeneration and vasculopathy in animal models of retinal diseases, examining the effects of different neuroprotective substances, ranging from nutraceuticals to antioxidants to neuropeptides and others and showing that reducing neuronal suffering also prevents overexpression of VEGF and vascular complications. Taken together, the reviewed evidence highlights the crucial role played by mediators such as VEGF in the relationship between retinal neuronal damage and vascular alterations and suggests that the use of neuroprotective substances could be an efficient strategy to prevent the onset or to retard the development of DR.

Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy

“…Among these factors, OS seems to play a prominent role as a major inducer of retinal VEGF, and here we demonstrate that OS can cause VEGF expression and release in sufficient amounts to trigger an autocrine loop leading to further VEGF release. In particular, considering that treatments with antioxidant compounds reduce the OS-induced VEGF upregulation in models of DR [ 6 ], the possibility exists that OS not only induces but also is involved in sustaining the VEGF autocrine loop. A major intracellular mediator involved in this mechanism is Nrf2, since its inhibition blocks the OS-induced increase of VEGF mRNA expression as demonstrated by the present results.…”

“…In particular, oxidative stress (OS) is likely to be a primary causative event in DR [ 3 ], and increased OS in retinal models has often been reported to cause VEGF overexpression. Conversely, treatments reducing OS have been found to also reduce VEGF expression [ 6 ].…”

The Multifunctionality of CD36 in Diabetes Mellitus and Its Complications—Update in Pathogenesis, Treatment and Monitoring

“…Neuronal damage is accompanied by increased expression and release of vascular endothelial growth factor (VEGF), which on the one hand is neuroprotective and on the other hand is a factor initiating neovascularization and PDR. In the classical approach, the main pathological roles are played by microvascular alterations, including the loss of pericytes and endothelial cells and basement membrane thickening, and the changes in the rheological properties of the blood, which together lead to capillary occlusion and degeneration [ 209 , 212 ]. DM not only causes damage to the retinal endothelial cells and inner blood-retinal barrier, but also a dysfunction of retinal pigment epithelium (RPE) layer expressed as disruption of transport by an outer blood-retina barrier (BRB) [ 213 ] and imbalance of secretions of cytokines, chemokines, and growth factors [ 214 ].…”

PACAP is Protective Against Cellular Stress in Retinal Pigment Epithelial Cells

“…Several papers suggest that DR is not only a vascular damage, but neurodegeneration also plays a pivotal role in its pathogenesis (Zhang et al 2013;Simo and Hernandez 2015;Rossino et al 2019). Various neuropeptides and their receptors, including VIP and PACAP, were detected in the retina (Nakamachi et al 2012) and proved to be neuroprotective against different harmful stimuli, thus they can be considered as potential therapeutic agents in DR (Atlasz et al 2010a, b;Nakamachi et al 2012;Lakk et al 2015;Shioda et al 2016;Ye et al 2019).…”