Electrotonic transmission in the retinal vasculature: inhibitory role of the diabetes/VEGF/aPKC pathway.
Animals; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Electric Conductivity; Endothelium, Vascular; Male; Patch-Clamp Techniques; Protein Kinase C; Rats, Long-Evans; Retinal Vessels; Signal Transduction; Vascular Endothelial Growth Factor A
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.
Shibata, M., Nakaizumi, A., & Puro, D. (2019). Electrotonic transmission in the retinal vasculature: inhibitory role of the diabetes/VEGF/aPKC pathway.. Physiol Rep, 7 (9). http://dx.doi.org/10.14814/phy2.14095