Of neurons and pericytes: The neuro-vascular approach to diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus and an increasingly common cause of visual impairment. Blood vessel damage occurs as the disease progresses, leading to ischemia, neovascularization, blood–retina barrier (BRB) failure and eventual blindness. Although detection and treatment strategies have improved considerably over the past years, there is room for a better understanding of the pathophysiology of the diabetic retina. Indeed, it has been increasingly realized that DR is in fact a disease of the retina’s neurovascular unit (NVU), the multi-cellular framework underlying functional hyperemia, coupling neuronal computations to blood flow. The accumulating evidence reveals that both neurochemical (synapses) and electrical (gap junctions) means of communications between retinal cells are affected at the onset of hyperglycemia, warranting a global assessment of cellular interactions and their role in DR. This is further supported by the recent data showing down-regulation of connexin 43 gap junctions along the vascular relay from capillary to feeding arteriole as one of the earliest indicators of experimental DR, with rippling consequences to the anatomical and physiological integrity of the retina. Here, recent advancements in our knowledge of mechanisms controlling the retinal neurovascular unit will be assessed, along with their implications for future treatment and diagnosis of DR.

Metabolomics of various samples advancing biomarker discovery and pathogenesis elucidation for diabetic retinopathy

“…After activating the synaptic receptor, extracellular glutamate is transferred into Müller cells by binding the glutamate aspartate transporter (GLAST), subsequently converted to glutamine under the action of the enzyme glutamine synthetase (GS) ( 111 ). Following this, glutamine is secreted into the extracellular space by Müller cells whereupon neurons can take in and then transform it into GABA or glutamate ( 112 ). Once this balance was disturbed, such as by hyperglycemia, accumulation of glutamate, reduced GS activity, and resultant loss of neuronal glutamine availability would be observed, which would lead to glutamate excitotoxicity, i.e., further retinal physiological disruptions that involved oxidative stress, inflammation, and neuronal apoptosis ( 112 , 113 ).…”

Connexins Signatures of the Neurovascular Unit and Their Physio-Pathological Functions

“…In an animal model of traumatic brain injury (TBI), it was observed that an impairment of platelet-derived growth factor-B (PDGF-B) signaling, resulting in a loss of pericyte–endothelium interaction and consequent neurovascular dysfunction, correlates with reduced levels of N-cadherin, adherent junction, and Cx43 functionality [ 175 ]. A noteworthy finding is the decline and/or reduction in Cx43–GJs along the arteriole–capillary vascular pathway; this is considered one of the first indicators of experimental diabetic retinopathy associated with reduced propagative vasomotor activity and cell coupling as well as compromised anatomical and physiological integrity of the retina [ 176 ].…”

The evolving role of long noncoding RNA HIF1A-AS2 in diabetic retinopathy: a cross-link axis between hypoxia, oxidative stress and angiogenesis via MAPK/VEGF-dependent pathway

“…Blood vessel damage arises with disease advancement, with subsequent ischemia, neovascularization, blood–retina barrier (BRB) disruption, and subsequent blindness. Though research work and treatment strategies have been established noticeably over the former years, there is a scope for an improved understanding of the pathophysiology and biochemical alterations concerning the disease [ 34 ].…”