Abstract
Loss of retinal blood flow autoregulation is an early feature of diabetes that precedes the development of clinically recognizable diabetic retinopathy (DR). Retinal blood flow autoregulation is mediated by the myogenic response of the retinal arterial vessels, a process that is initiated by the stretch‑dependent activation of TRPV2 channels on the retinal vascular smooth muscle cells (VSMCs). Here, we show that the impaired myogenic reaction of retinal arterioles from diabetic animals is associated with a complete loss of stretch‑dependent TRPV2 current activity on the retinal VSMCs. This effect could be attributed, in part, to TRPV2 channel downregulation, a phenomenon that was also evident in human retinal VSMCs from diabetic donors. We also demonstrate that TRPV2 heterozygous rats, a nondiabetic model of impaired myogenic reactivity and blood flow autoregulation in the retina, develop a range of microvascular, glial, and neuronal lesions resembling those observed in DR, including neovascular complexes. No overt kidney pathology was observed in these animals. Our data suggest that TRPV2 dysfunction underlies the loss of retinal blood flow autoregulation in diabetes and provide strong support for the hypothesis that autoregulatory deficits are involved in the pathogenesis of DR.
Original language | English |
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Article number | e155128 |
Number of pages | 19 |
Journal | JCI Insight |
Volume | 7 |
Issue number | 18 |
DOIs | |
Publication status | Published - 22 Sept 2022 |
Bibliographical note
Acknowledgments:This study was supported by grants from the Biotechnology and Biological Sciences Research Council (BB/I026359/1); Department for the Economy (DfE; Northern Ireland); Diabetes UK (18/0005791); MRC Confidence in Concept award (RGD 24860); Health & Social Care R&D Division, Northern Ireland (STL/4748/13); Medical Research Council (MC_PC_15026); and Fight for Sight, UK (5031/5032). The graphical abstract for this paper was created using BioRender.
Keywords
- Animals
- Arterioles
- Diabetes Mellitus
- Diabetic Retinopathy
- Homeostasis/physiology
- Humans
- Rats
- Retinal Artery
- Retinal Vessels
- TRPV Cation Channels/genetics