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Published in: Graefe's Archive for Clinical and Experimental Ophthalmology 1/2019

Open Access 01-01-2019 | Basic Science

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

Authors: Polina Lizunkova, Emmanuella Enuwosa, Havovi Chichger

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 1/2019

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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.
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Literature
1.
go back to reference Ogurtsova K, da Rocha Fernandes JD, Huang Y et al (2017) IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 128:40–50CrossRefPubMed Ogurtsova K, da Rocha Fernandes JD, Huang Y et al (2017) IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 128:40–50CrossRefPubMed
3.
go back to reference Mohamed Q, Gillies MC, Wong TY (2007) Management of diabetic retinopathy: a systematic review. JAMA 298(8):902–916CrossRefPubMed Mohamed Q, Gillies MC, Wong TY (2007) Management of diabetic retinopathy: a systematic review. JAMA 298(8):902–916CrossRefPubMed
6.
go back to reference Simo R, Carrasco E, Garcia-Ramirez M et al (2006) Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev 2(1):71–98CrossRefPubMed Simo R, Carrasco E, Garcia-Ramirez M et al (2006) Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev 2(1):71–98CrossRefPubMed
8.
go back to reference Ozturk BT, Bozkurt B, Kerimoglu H et al (2009) Effect of serum cytokines and VEGF levels on diabetic retinopathy and macular thickness. Mol Vis 15:1906–1914PubMedPubMedCentral Ozturk BT, Bozkurt B, Kerimoglu H et al (2009) Effect of serum cytokines and VEGF levels on diabetic retinopathy and macular thickness. Mol Vis 15:1906–1914PubMedPubMedCentral
11.
go back to reference Lim LS, Cheung CMG, Mitchell P et al (2011) Emerging evidence concerning systemic safety of anti-VEGF agents--should ophthalmologists be concerned? Am J Ophthalmol 152(3):329–331CrossRefPubMed Lim LS, Cheung CMG, Mitchell P et al (2011) Emerging evidence concerning systemic safety of anti-VEGF agents--should ophthalmologists be concerned? Am J Ophthalmol 152(3):329–331CrossRefPubMed
13.
go back to reference Nelson G, Hoon MA, Chandrashekar J et al (2001) Mammalian sweet taste receptors. Cell 106(3):381–390CrossRefPubMed Nelson G, Hoon MA, Chandrashekar J et al (2001) Mammalian sweet taste receptors. Cell 106(3):381–390CrossRefPubMed
17.
go back to reference Im E, Kazlauskas A (2007) Src family kinases promote vessel stability by antagonizing the rho/ROCK pathway. J Biol Chem 282(40):29122–29129CrossRefPubMed Im E, Kazlauskas A (2007) Src family kinases promote vessel stability by antagonizing the rho/ROCK pathway. J Biol Chem 282(40):29122–29129CrossRefPubMed
22.
go back to reference Cui J, Gong R, Hu S et al (2018) Gambogic acid ameliorates diabetes-induced proliferative retinopathy through inhibition of the HIF-1alpha/VEGF expression via targeting PI3K/AKT pathway. Life Sci 192:293–303CrossRefPubMed Cui J, Gong R, Hu S et al (2018) Gambogic acid ameliorates diabetes-induced proliferative retinopathy through inhibition of the HIF-1alpha/VEGF expression via targeting PI3K/AKT pathway. Life Sci 192:293–303CrossRefPubMed
26.
go back to reference Quinn TP, Peters KG, Vries CD et al (1993) Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A 90(16):7533–7537CrossRefPubMedPubMedCentral Quinn TP, Peters KG, Vries CD et al (1993) Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A 90(16):7533–7537CrossRefPubMedPubMedCentral
27.
go back to reference Basagiannis D, Zografou S, Murphy C et al (2016) VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis. J Cell Sci 129(21):4091–4104PubMed Basagiannis D, Zografou S, Murphy C et al (2016) VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis. J Cell Sci 129(21):4091–4104PubMed
28.
go back to reference Chen J, Somanath PR, Razorenova O et al (2005) Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat Med 11(11):1188–1196CrossRefPubMedPubMedCentral Chen J, Somanath PR, Razorenova O et al (2005) Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat Med 11(11):1188–1196CrossRefPubMedPubMedCentral
30.
go back to reference Mace OJ, Affleck J, Patel N et al (2007) Sweet taste receptors in rat small intestine stimulate glucose absorption through apical GLUT2. J Physiol Lond 582(Pt 1):379–392CrossRefPubMedPubMedCentral Mace OJ, Affleck J, Patel N et al (2007) Sweet taste receptors in rat small intestine stimulate glucose absorption through apical GLUT2. J Physiol Lond 582(Pt 1):379–392CrossRefPubMedPubMedCentral
31.
go back to reference Gardner C, Wylie-Rosett J, Gidding SS et al (2012) Nonnutritive sweeteners: current use and health perspectives: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 126(4):509–519CrossRefPubMed Gardner C, Wylie-Rosett J, Gidding SS et al (2012) Nonnutritive sweeteners: current use and health perspectives: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 126(4):509–519CrossRefPubMed
33.
go back to reference Roberts A, Renwick AG, Sims J et al (2000) Sucralose metabolism and pharmacokinetics in man. Food Chem Toxicol 38(Suppl 2):31CrossRef Roberts A, Renwick AG, Sims J et al (2000) Sucralose metabolism and pharmacokinetics in man. Food Chem Toxicol 38(Suppl 2):31CrossRef
34.
go back to reference Sweatman TW, Renwick AG, Burgess CD (1981) The pharmacokinetics of saccharin in man. Xenobiotica 11(8):531–540CrossRefPubMed Sweatman TW, Renwick AG, Burgess CD (1981) The pharmacokinetics of saccharin in man. Xenobiotica 11(8):531–540CrossRefPubMed
35.
go back to reference Shakib M, Cunha-Vaz JG (1966) Studies on the permeability of the blood-retinal barrier. IV Junctional complexes of the retinal vessels and their role in the permeability of the blood-retinal barrier. Exp Eye Res 5(3):229–234CrossRefPubMed Shakib M, Cunha-Vaz JG (1966) Studies on the permeability of the blood-retinal barrier. IV Junctional complexes of the retinal vessels and their role in the permeability of the blood-retinal barrier. Exp Eye Res 5(3):229–234CrossRefPubMed
36.
go back to reference Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250CrossRefPubMed Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250CrossRefPubMed
37.
go back to reference Holmes K, Roberts OL, Thomas AM et al (2007) Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 19(10):2003–2012CrossRefPubMed Holmes K, Roberts OL, Thomas AM et al (2007) Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 19(10):2003–2012CrossRefPubMed
41.
go back to reference Guertin DA, Stevens DM, Thoreen CC et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11(6):859–871CrossRefPubMed Guertin DA, Stevens DM, Thoreen CC et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11(6):859–871CrossRefPubMed
42.
Metadata
Title
Activation of the sweet taste receptor T1R3 by sucralose attenuates VEGF-induced vasculogenesis in a cell model of the retinal microvascular endothelium
Authors
Polina Lizunkova
Emmanuella Enuwosa
Havovi Chichger
Publication date
01-01-2019
Publisher
Springer Berlin Heidelberg
Published in
Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 1/2019
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-018-4157-8

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