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Loss of TRPV2-mediated blood flow autoregulation recapitulates diabetic retinopathy in rats
Michael O’Hare, … , J. Graham McGeown, Tim M. Curtis
Michael O’Hare, … , J. Graham McGeown, Tim M. Curtis
Published September 22, 2022
Citation Information: JCI Insight. 2022;7(18):e155128. https://doi.org/10.1172/jci.insight.155128.
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Research Article Ophthalmology Vascular biology

Loss of TRPV2-mediated blood flow autoregulation recapitulates diabetic retinopathy in rats

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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.

Authors

Michael O’Hare, Gema Esquiva, Mary K. McGahon, Jose Manuel Romero Hombrebueno, Josy Augustine, Paul Canning, Kevin S. Edgar, Peter Barabas, Thomas Friedel, Patrizia Cincolà, Jennifer Henry, Katie Mayne, Hannah Ferrin, Alan W. Stitt, Timothy J. Lyons, Derek P. Brazil, David J. Grieve, J. Graham McGeown, Tim M. Curtis

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Figure 2

TRPV2 expression and function in diabetic retinal arterioles.

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TRPV2 expression and function in diabetic retinal arterioles.
(A) Trpv2 ...
(A) Trpv2 mRNA expression in diabetic retinal arterioles expressed as a fold change from nondiabetic control values. *P < 0.05 based on Mann–Whitney U test; n = 9 animals per group. (B) Left, confocal images of nondiabetic and diabetic retinal arterioles embedded within retinal whole mount preparations and labeled for TRPV2 (green), α-SMA (red), and TO-PRO-3 nuclear stain (pseudocolored blue). Most of the TRPV2 staining localized to border regions between the adjacent retinal VSMCs, which we have previously shown correspond to the VSMC plasma membranes (16). Scale bars: 10 μm. Right, TRPV2 fluorescence intensity in diabetic retinal VSMCs expressed relative to nondiabetic controls. *P < 0.05 based on Mann–Whitney U test; n = 6 animals, n = 6 arterioles per group. (C) Left, on-cell patch-clamp recordings from nondiabetic and diabetic retinal arterioles with the TRPV2 agonist, Δ9-THC (10 μM; Tocris) included in the patch pipette. Traces in the lower panels are from arterioles that were preincubated for 1 hour with TRPV2 pore-blocking antibodies (1:100; Alomone, ACC-039). Right, box-and-whisker plots showing that Δ9-THC–induced currents were significantly smaller in diabetic compared with nondiabetic arterioles. **P < 0.01, ****P < 0.0001 based on 2-way ANOVA; n = 5–9 animals, n = 5–13 arterioles per group. (D) Left, confocal cross-sectional images of human nondiabetic and diabetic retinal arterioles labeled for TRPV2 (green) and α-SMA (red). Scale bars: 15 μm. Right, Summary data showing that TRPV2-associated immunofluorescence, but not α-SMA–associated immunofluorescence, was significantly lower in human diabetic retinal VSMCs. *P < 0.05 based on Mann–Whitney U test; n = 4 postmortem donors, n = 16 arterioles per group.

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