Abstract
The deleterious impact of diabetes on the retina is a leading cause of vision loss. Ultimately, the hypoxic retinopathy caused by diabetes results in irreversible damage to vascular, neuronal, and glial cells. Less understood is how retinal physiology is altered early in the course of diabetes. We recently found that the electrotonic architecture of the retinovasculature becomes fundamentally altered soon after the onset of this disorder. Namely, the spread of voltage through the vascular endothelium is markedly inhibited. The goal of this study was to elucidate how diabetes inhibits electrotonic transmission. We hypothesized that vascular endothelial growth factor (VEGF) may play a role since its upregulation in hypoxic retinopathy is associated with sight‐impairing complications. In this study, we quantified voltage transmission between pairs of perforated‐patch pipettes sealed onto abluminal cells located on retinal microvascular complexes freshly isolated from diabetic and nondiabetic rats. We report that exposure of diabetic retinal microvessels to an anti‐VEGF antibody or to a small‐molecule inhibitor of atypical PKCs (aPKC) near‐fully restored the efficacy of electrotonic transmission. Furthermore, exposure of nondiabetic microvessels to VEGF mimicked, via a mechanism sensitive to the aPKC inhibitor, the diabetes‐induced inhibition of transmission. Thus, activation of the diabetes/VEGF/aPKC pathway switches the retinovasculature from a highly interactive operational unit to a functionally balkanized complex. By delimiting the dissemination of voltage‐changing vasomotor inputs, this organizational fragmentation is likely to compromise effective regulation of retinal perfusion. Future pharmacological targeting of the diabetes/VEGF/aPKC pathway may serve to impede progression of vascular dysfunction to irreversible diabetic retinopathy.
Highlights
The constellation of injurious effects of diabetes on the vascular, glial, and neuronal components of the retina ranks as a leading cause of visual impairment
vascular endothelial growth factor (VEGF) was of interest since its upregulation is known to play a role in diabetic retinopathy (Antonetti et al 2012; Jiang et al 2015; Kida et al 2017) and gap junction-dependent intercellular communication in various nonretinal vascular cells can be inhibited by VEGF (Suarez and Ballmer-Hofer 2001; Thuringer 2004; Nimlamool et al 2015)
Using dual perforated-patch recordings from microvessels freshly isolated from the retinas of rats made diabetic by streptozotocin, we demonstrated that exposure to an anti-VEGF
Summary
The constellation of injurious effects of diabetes on the vascular, glial, and neuronal components of the retina ranks as a leading cause of visual impairment. A distinctive adaptation is the low density of microvessels within the retina (Funk 1997). Even though this sparseness minimizes vascular interference with photons passing to the photoreceptors, the paucity of vessels leaves little functional reserve for maintaining adequate perfusion to meet the stringent metabolic requirements of the retinal neurons. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
