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        Dysregulation of TRPV4, eNOS and caveolin-1 contribute to endothelial dysfunction in the streptozotocin rat model of diabetes

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        Revised_style_Shamsaldeen_et_al_LL_Accepted_EJP_july_2020.pdf (PDF, 6Mb)
        Author
        Shamsaldeen, Yousif
        Lione, Lisa
        Benham, Christopher
        Attention
        2299/23663
        Abstract
        Endothelial dysfunction is a common complication in diabetes in which endothelium-dependent vasorelaxation is impaired. The aim of this study was to examine the involvement of the TRPV4 ion channel in type 1 diabetic endothelial dysfunction and the possible association of endothelial dysfunction with reduced expression of TRPV4, endothelial nitric oxide synthase (eNOS) and caveolin-1. Male Wistar rats (350–450 g) were injected with 65mg/kg i.p. streptozotocin (STZ) or vehicle. Endothelial function was investigated in aortic rings and mesenteric arteries using organ bath and myograph, respectively. TRPV4 function was studied with fura-2 calcium imaging in endothelial cells cultured from aortas from control and STZ treated rats. TRPV4, caveolin-1 and eNOS expression was investigated in these cells using immunohistochemistry. STZ-treated diabetic rats showed significant endothelial dysfunction characterised by impaired muscarinic-induced vasorelaxation (aortic rings: STZ-diabetics: Emax= 29.6±9.3%; control: Emax=77.2±2.5% P˂0.001), as well as significant impairment in TRPV4-induced vasorelaxation (aortic rings, 4αPDD STZ-diabetics: Emax= 56.0±5.5%; control: Emax= 81.1±2.1% P˂0.001). Furthermore, STZ-diabetic primary aortic endothelial cells showed a significant reduction in TRPV4-induced intracellular calcium elevation (P˂0.05) compared with the control group. This was associated with significantly lower expression of TRPV4, caveolin-1 and eNOS and this was reversed by insulin treatment of the endothelial cultures from STZ -diabetic rats. Taken together, these data are consistent with the hypothesis that signalling through TRPV4, caveolin-1, and eNOS is downregulated in STZ-diabetic aortic endothelial cells and restored by insulin treatment.
        Publication date
        2020-12-05
        Published in
        European Journal of Pharmacology
        Published version
        https://doi.org/10.1016/j.ejphar.2020.173441
        Other links
        http://hdl.handle.net/2299/23663
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