Vascular effects of sphingolipids

Michel, Martin C.; Mulders, Arthur C. M.; Jongsma, M.A.; Alewijnse, Astrid E.; Peters, Stephan L. M.

doi:10.1111/j.1651-2227.2007.00207.x

Cited by 33 publications

(27 citation statements)

References 64 publications

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“…25). Although signaling through S1P 2 and S1P 3 receptors has been shown to contribute to S1P-induced vasoconstriction (22,42,43), the present results obtained in S1P 2 and S1P 3 receptornull aortic VSMCs and in VSMCs in which S1P 1 was inhibited with VPC23019 demonstrate that S1P can signal either via other receptors or via intracellular mechanisms to induce SOCE.…”

Section: Discussioncontrasting

confidence: 46%

S1P activates store-operated calcium entry via receptor- and non-receptor-mediated pathways in vascular smooth muscle cells

Hopson

Truelove

Chun

et al. 2011

American Journal of Physiology-Cell Physiology

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Sphingosine-1-phosphate (S1P) has been shown to modulate intracellular Ca(2+) through both G protein-coupled receptors and intracellular second messenger pathways. The precise mechanism by which S1P activates store-operated calcium entry (SOCE) in vascular smooth muscle cells (VSMCs) has not been fully characterized. Because sphingolipids and Ca(2+) modulate proliferation and constriction in VSMCs, characterizing the connection between S1P and SOCE may provide novel therapeutic targets for vascular diseases. We found that S1P triggered STIM1 puncta formation and SOCE in VSMCs. S1P-activated SOCE was inhibited by 2-aminoethoxydiphenyl borate (2-APB), diethylstilbestrol (DES), and gadolinium (Gd(3+)). SOCE was observed in VSMCs lacking either S1P(2) or S1P(3) receptors, suggesting that S1P acts via multiple signaling pathways. Indeed, both extracellular and intracellular S1P application increased the total internal reflection fluorescence signal in VSMCs cells transfected with STIM1-yellow fluorescent protein in a 2-APB-sensitive manner. These data, and the fact that 2-APB, DES, and Gd(3+) all inhibited S1P-induced cerebral artery constriction, suggest that SOCE modulates S1P-induced vasoconstriction in vivo. Finally, S1P-induced SOCE was larger in proliferative than in contractile VSMCs, correlating with increases in STIM1, Orai1, S1P(1), and S1P(3) receptor mRNA. These data demonstrate that S1P can act through both receptors and a novel intracellular pathway to activate SOCE. Because S1P-induced SOCE contributes to vessel constriction and is increased in proliferative VSMCs, it is likely that S1P/SOCE signaling in proliferative VSMCs may play a role in vascular dysfunction such as atherosclerosis and diabetes.

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Section: Discussioncontrasting

confidence: 46%

S1P activates store-operated calcium entry via receptor- and non-receptor-mediated pathways in vascular smooth muscle cells

Hopson

Truelove

Chun

et al. 2011

American Journal of Physiology-Cell Physiology

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“…Furthermore, dietary SM plays an important role in neonatal gut maturation during the suckling period of rats and contributes to the myelination of the developing rat central nervous system (CNS) (Oshida et al, 2003). Michel, Mulders, Jongsma, Alewijnse, and Peters (2007) also suggested that SM metabolites are important endogenous modulators of vascular function, which may contribute to the pathophysiology of some diseases.…”

Section: Polar Lipids Sphingolipids and Metabolitesmentioning

confidence: 99%

Nutritional and technological aspects of milk fat globule membrane material

Dewettinck

Rombaut

Thienpont

et al. 2008

International Dairy Journal

472

424

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“…It already has been demonstrated that lysosphingolipids can affect cellular proliferation via interference in signal transduction. For example, sphingosine-1-phosphate is known to stimulate proliferation of smooth muscle cells by a variety of signal transduction pathways including ERK and MAPK (39,40).…”

Section: Discussionmentioning

confidence: 99%

Elevated globotriaosylsphingosine is a hallmark of Fabry disease

Aerts

Groener

Kuiper

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

626

565

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Fabry disease is an X-linked lysosomal storage disease caused by deficiency of ␣-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of ␣-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.

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Vascular effects of sphingolipids

Abstract: We conclude that sphingomyelin metabolites are important endogenous modulators of vascular function, which may contribute to the pathophysiology of some diseases and be targets for therapeutic interventions.

Cited by 33 publications

References 64 publications

S1P activates store-operated calcium entry via receptor- and non-receptor-mediated pathways in vascular smooth muscle cells

S1P activates store-operated calcium entry via receptor- and non-receptor-mediated pathways in vascular smooth muscle cells

Nutritional and technological aspects of milk fat globule membrane material

Elevated globotriaosylsphingosine is a hallmark of Fabry disease

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