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Michael O'Hare, Mary McGahon, Hannah Ferrin, Graham McGeown, Tim Curtis; Diabetes impairs TRPV2 channel activity in rat retinal arterioles.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4052.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal blood flow autoregulation has been shown to be disrupted in diabetic subjects prior to the onset of clinically evident retinopathy. It is known that the myogenic response is a crucial contributor to blood flow autoregulation in the retina. Recent studies from our group have shown that TRPV2 channels on retinal vascular smooth muscle cells (VSMCs) contribute to stretch-activated cation currents and myogenic constriction in retinal arterioles. We tested the hypothesis that the disruption of retinal arteriolar myogenic signalling during diabetes results from the impairment of TRPV2 channel activity.
The expression and functional activity of TRPV2 channels was compared in retinal arterioles isolated from streptozotocin-induced diabetic rats of 3-months disease duration and aged-matched control animals. mRNA and protein expression for TRPV2 was assessed using real-time RT-PCR and confocal immunolabelling, respectively. TRPV2 functional activity was determined using patch-clamp electrophysiology and arteriolar pressure myography.
mRNA transcript levels for TRPV2 were ~45% lower in retinal arterioles from diabetic rats. Confocal imaging revealed clustering of TRPV2 channels within the cytosol and on the plasma membrane of retinal VSMCs. TRPV2 channel clusters were reduced in retinal VSMCs from diabetic rats (P<0.01). The extent of the reduction was similar to that observed for TRPV2 mRNA levels, although clusters of TRPV2 channels were still present on the plasma membrane of diabetic VSMCs. Stretch-activated TRPV2 channel activity was completely abolished in cell-attached patch-clamp recordings from diabetic VSMCs (P<0.01). When pressurised to 40mmHg, isolated retinal arterioles from control animals developed myogenic tone that was reversed in the presence of the TRPV2 inhibitor, tranilast (100µM). Retinal arterioles from diabetic animals failed to develop myogenic tone and were insensitive to tranilast exposure.
Our data suggest that TRPV2 channels are downregulated in retinal arterioles from diabetic animals and that the mechanisms that link membrane stretch to TRPV2 channel activation are also disrupted. These changes may explain why pressure autoregulation of blood flow is impaired in the diabetic retina.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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