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

Abstract

Endothelial dysfunction is a common complication in diabetes in which endotheliumdependent 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 STZdiabetic aortic endothelial cells and restored by insulin treatment.

A meta-analysis of the effects of endothelial nitric oxide synthase 4ba polymorphism on renal interstitial fibrosis in diabetic nephropathy

“…However, the specific mechanisms of the occurrence of renal interstitial fibrosis and the progression of uremia are not entirely clear (25). Relevant studies have revealed that vascular endothelial dysfunction caused by NOS damage is a key factor for DN (26). Therefore, compound logic retrieval Boolean logic retrieval method was employed, and a metaanalysis was implemented of 13 studies involving DN patients as the experimental group and non-nephropathy diabetic patients or healthy individuals as controls.…”

The Transient Receptor Potential Vanilloid 4 Channel and Cardiovascular Disease Risk Factors

“…Although the underlying mechanism of TRPV4 downregulation in diabetes is not known, a recent finding by Shamsaldeen et al (2020) may provide a clue. In the aortas of STZ-induced diabetic rats with endothelial dysfunction, the reduction in TRPV4 expression was accompanied by a reduction in both eNOS and caveolin-1 expression; insulin treatment reversed the endothelial dysfunction and was associated with the upregulation of TRPV4 expression, eNOS and caveolin-1 ( Shamsaldeen et al, 2020 ).…”

“…Moreover, in blood vessels from animal models of diabetes, reduced TRPV4 expression has been consistently reported across numerous studies. These blood vessels include mesenteric arteries ( Ma et al, 2013 ), retinal arterioles ( Monaghan et al, 2015 ), and aortas ( Shamsaldeen et al, 2020 ) of streptozotocin (STZ)-induced diabetic rats, as well as in aortas of STZ-induced diabetic mice and db/db mice ( Gao et al, 2020 ). Furthermore, the reduction in TRPV4 expression was consistently associated with a decrease in agonist-stimulated Ca 2+ influx in endothelial cells, which led to an impairment of either NO ( Gao et al, 2020 ; Shamsaldeen et al, 2020 )- or EDH ( Ma et al, 2013 )-mediated vasorelaxation, depending on the vascular bed studied.…”

“…These blood vessels include mesenteric arteries ( Ma et al, 2013 ), retinal arterioles ( Monaghan et al, 2015 ), and aortas ( Shamsaldeen et al, 2020 ) of streptozotocin (STZ)-induced diabetic rats, as well as in aortas of STZ-induced diabetic mice and db/db mice ( Gao et al, 2020 ). Furthermore, the reduction in TRPV4 expression was consistently associated with a decrease in agonist-stimulated Ca 2+ influx in endothelial cells, which led to an impairment of either NO ( Gao et al, 2020 ; Shamsaldeen et al, 2020 )- or EDH ( Ma et al, 2013 )-mediated vasorelaxation, depending on the vascular bed studied. Taken together, these findings strongly indicate that downregulation of TRPV4 expression contributes to the endothelial dysfunction associated with diabetes.…”

Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity

“…Also, Al-brakati et al [ 211 ] have demonstrated that caveolar disturbance results in decreased NO in femoral arteries. A study by Shamsaldeen et al [ 212 ] has shown a decreased expression of eNOS and Cav-1 in the streptozotocin type I diabetic rat model. These disturbances in caveolae can decrease the levels of Cav-1 associated with eNOS, thereby undermining vascular function.…”