Dataset Information

Activation of the sweet taste receptor T1R3 by sucralose attenuates VEGF-induced vasculogenesis in a cell model of the retinal microvascular endothelium.

ABSTRACT: BACKGROUND:One of the most prevalent microvascular complications for patients with diabetes is diabetic retinopathy (DR) associated with increased retinal endothelial blood vessel formation. Treatments to reduce vascularisation in the retinal endothelium are linked to improved sight in patients with DR. Recently, we have demonstrated the novel protective role of the artificial sweetener, sucralose, and the sweet taste receptor, T1R3, in the pulmonary endothelium to reduce vascular leak. In the present study, we examined the role of sucralose and sweet taste receptors on vasculogenic processes (proliferation, migration, adhesion and tube formation) in a cell model of the retinal endothelium. METHODS:We exposed human retinal microvascular endothelial cells (RMVEC) to VEGF as an in vitro model of DR in the presence and absence of T1R3 agonist sucralose. RESULTS:In RMVEC, we observed increased VEGF-induced cell proliferation, migration, adhesion and tube formation, which was significantly attenuated by exposure to the artificial sweetener sucralose. Following siRNA knockdown of the sweet taste receptor, T1R3, but not T1R2, the protective effect of sucralose on VEGF-induced RMVEC vasculogenic processes was blocked. We further demonstrate that sucralose attenuates VEGF-induced Akt phosphorylation to protect the retinal microvasculature. CONCLUSION:These studies are the first to demonstrate a protective effect of an artificial sweetener, through the sweet taste receptor T1R3, on VEGF-induced vasculogenesis in a retinal microvascular endothelial cell line.

SUBMITTER: Lizunkova P

PROVIDER: S-EPMC6323138 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Activation of the sweet taste receptor T1R3 by sucralose attenuates VEGF-induced vasculogenesis in a cell model of the retinal microvascular endothelium.

Lizunkova Polina P Enuwosa Emmanuella E Chichger Havovi H

Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 20181023 1

<h4>Background</h4>One of the most prevalent microvascular complications for patients with diabetes is diabetic retinopathy (DR) associated with increased retinal endothelial blood vessel formation. Treatments to reduce vascularisation in the retinal endothelium are linked to improved sight in patients with DR. Recently, we have demonstrated the novel protective role of the artificial sweetener, sucralose, and the sweet taste receptor, T1R3, in the pulmonary endothelium to reduce vascular leak. ...[more]

PMID: 30353220

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Project description:A hallmark of acute respiratory distress syndrome (ARDS) is pulmonary vascular permeability. In these settings, loss of barrier integrity is mediated by cell-contact disassembly and actin remodeling. Studies into molecular mechanisms responsible for improving microvascular barrier function are therefore vital in the development of therapeutic targets for reducing vascular permeability in ARDS. The sweet taste receptor T1R3 is a G protein-coupled receptor, activated following exposure to sweet molecules, to trigger a gustducin-dependent signal cascade. In recent years, extraoral locations for T1R3 have been identified; however, no studies have focused on T1R3 within the vasculature. We hypothesize that activation of T1R3, in the pulmonary vasculature, plays a role in regulating endothelial barrier function in settings of ARDS. Our study demonstrated expression of T1R3 within the pulmonary vasculature, with a drop in expression levels following exposure to barrier-disruptive agents. Exposure of lung microvascular endothelial cells to the intensely sweet molecule sucralose attenuated LPS- and thrombin-induced endothelial barrier dysfunction. Likewise, sucralose exposure attenuated bacteria-induced lung edema formation in vivo. Inhibition of sweet taste signaling, through zinc sulfate, T1R3, or G-protein siRNA, blunted the protective effects of sucralose on the endothelium. Sucralose significantly reduced LPS-induced increased expression or phosphorylation of the key signaling molecules Src, p21-activated kinase (PAK), myosin light chain-2 (MLC2), heat shock protein 27 (HSP27), and p110α phosphatidylinositol 3-kinase (p110αPI3K). Activation of T1R3 by sucralose protects the pulmonary endothelium from edemagenic agent-induced barrier disruption, potentially through abrogation of Src/PAK/p110αPI3K-mediated cell-contact disassembly and Src/MLC2/HSP27-mediated actin remodeling. Identification of sweet taste sensing in the pulmonary vasculature may represent a novel therapeutic target to protect the endothelium in settings of ARDS.

Project description:Outbred rats display variable preferences for bittersweet solutions, expressed as preference or avoidance of high concentrations of artificial sweeteners over water. This may reflect individual differences in appetitive/aversive conflict processing that may have predictive validity for disorders of motivation. Here we use a homecage two-bottle choice procedure to examine the test/retest stability and between-tastant consistency in sucralose preference to determine the reliability of bittersweet taste preference. Sucralose is a non-caloric artificial sweetener that is preferred by some rats and avoided by others. We sought to determine whether sucralose preference is consistent with preference of sucrose/quinine solutions that have known sweet and bitter taste qualities, respectively. We give fluid restricted rats 45-minutes homecage access to water and ascending concentrations of sucralose (SUCRA; 0.0025-10mM) or a compound solution of sucrose (116mM) + quinine (0.002-2mM) (SQ). We use a within-subject counterbalanced design (SUCRA or SQ testing) to determine preference of each bittersweet solution relative to water. We observed individual variability in preference for SUCRA and SQ, such that some rats preferred bittersweet solutions over water (preferring) while other rats preferred water over bittersweet solutions (avoiding). Within tastant, this preference remained stable across repeated testing. Between solutions, SUCRA preference scores correlated with SQ scores, suggesting consistent taste conflict processing for both bittersweet solutions. Population level analyses confirmed that preference generalizes across bittersweet solutions, and that rats' preferences for bittersweet solutions relative to water are stable over time. The test/retest and between-tastant reliability of this taste conflict screening procedure support the potential utility of this model for exploring individual variability in appetitive/aversive conflict processes mediating motivated behavior.

Dataset Information

Activation of the sweet taste receptor T1R3 by sucralose attenuates VEGF-induced vasculogenesis in a cell model of the retinal microvascular endothelium.

Publications

Activation of the sweet taste receptor T1R3 by sucralose attenuates VEGF-induced vasculogenesis in a cell model of the retinal microvascular endothelium.

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