Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient

Yanagida, K.; Hla, Timothy

doi:10.1146/annurev-physiol-021014-071635

Cited by 92 publications

(87 citation statements)

References 166 publications

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“…High levels (∼1 μM) of S1P are found in blood, and more than half of plasma S1P is associated with high-density lipoprotein (HDL) (44). Importantly, lower plasma concentrations of HDL were reported to be associated with dementia (45).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, S1P 1 activity may also be regulated from the abluminal side by circulating S1P. In the lymphoid organs, multiple perivascular cellular components maintain local perivascular S1P gradients, which are important for immune cell trafficking (44). Recent studies suggest the highly dynamic nature of BBB during the sleep-awake cycle (48).…”

Section: Discussionmentioning

confidence: 99%

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Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Yanagida

Liu

Faraco

et al. 2017

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

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178

165

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The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood-brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1-phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specific S1pr1 knockout mice (S1pr1 iECKO ) showed BBB breach for small-molecular-mass fluorescence tracers (<3 kDa), but not larger tracers (>10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels of S1pr1 iECKO mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P 1 function led to transient BBB breach. These data suggest that brain endothelial S1P 1 maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P 1 inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.blood-brain barrier | sphingosine 1-phosphate | endothelium | tight junction | drug delivery

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Yanagida

Liu

Faraco

et al. 2017

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

Self Cite

178

165

View full text Add to dashboard Cite

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“…S1P can signal in two distinct ways, either through binding to one of five S1P-specific G-protein coupled receptors, or as an intracellular second messenger, although the latter is not a well understood mechanism. S1P and its producing enzymes have been implicated in a host of biological and pathophysiological roles, including cancer biology, inflammation, immune responses, vascular biology, and many others [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

An intrinsic lipid-binding interface controls sphingosine kinase 1 function

Pulkoski-Gross

Jenkins

Truman

et al. 2018

Journal of Lipid Research

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Sphingosine kinase 1 (SK1) is required for production of sphingosine-1-phosphate (S1P) and thereby regulates many cellular processes-including cellular growth, immune cell trafficking, and inflammation. To produce S1P, SK1 must access sphingosine directly from membranes. However, the molecular mechanisms underlying SK1's direct membrane interactions remain unclear. We used hydrogen-deuterium exchange mass spectrometry to study interactions of SK1 with membrane vesicles. Using the CRISPR/Cas9 technique to generate HCT116 cells lacking SK1, we explored the effects of membrane interface disruption and the function of the SK1 interaction site. Disrupting the interface resulted in reduced membrane association and decreased cellular SK1 activity. Moreover, SK1-dependent signaling, including cell invasion and endocytosis, was abolished upon mutation of the membrane-binding interface. Of note, we identified a positively charged motif on SK1 that is responsible for electrostatic interactions with membranes. Furthermore, we demonstrated that SK1 uses a single contiguous interface, consisting of an electrostatic site and a hydrophobic site, to interact with membrane-associated anionic phospholipids. Altogether, these results define a composite domain in SK1 that regulates its intrinsic ability to bind membranes and indicate that this binding is critical for proper SK1 function. This work will allow for a new line of thinking for targeting SK1 in disease.

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“…Altogether, these observations demonstrate that identifying novel actors in the maintenance of vascular integrity remains a crucial challenge to restore heart function. In particular, the lipid mediator sphingosine-1-phosphate (S1P) has recently emerged as a potent mediator of vascular integrity (9,10). In addition, the bioactive peptide apelin is a critical player in both lymphangiogenesis and angiogenesis (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%