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Circulating sphingosine-1-phosphate depletion is associated with endothelial activation and altered brain-endothelial S1P pathway expression in ischemic stroke

Porschen, Lisa Teresa LU ; Matthes, Frank LU orcid ; Matuskova, Hana LU ; Braadt, Lino ; Petzold, Gabor C ; Lindgren, Arne LU and Meissner, Anja LU orcid (2026) In Fluids and Barriers of the CNS 23.
Abstract
Background
Ischemic stroke remains a leading cause of disability and mortality worldwide, with limited acute therapeutic options. Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates endothelial function, vascular integrity, and immune responses, and reduced circulating S1P levels have been reported in ischemic stroke. Whether plasma S1P depletion parallels alterations in brain-endothelial S1P metabolism, receptor expression, and endothelial activation, however, remains unclear. Here, we characterized circulating S1P levels together with stroke-associated changes in brain-endothelial S1P pathway expression, markers related to endothelial activation, and blood-brain barrier (BBB)... (More)
Background
Ischemic stroke remains a leading cause of disability and mortality worldwide, with limited acute therapeutic options. Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates endothelial function, vascular integrity, and immune responses, and reduced circulating S1P levels have been reported in ischemic stroke. Whether plasma S1P depletion parallels alterations in brain-endothelial S1P metabolism, receptor expression, and endothelial activation, however, remains unclear. Here, we characterized circulating S1P levels together with stroke-associated changes in brain-endothelial S1P pathway expression, markers related to endothelial activation, and blood-brain barrier (BBB) integrity.

Methods
We quantified plasma S1P concentrations in patients with acute ischemic stroke (n = 50) and age- and sex-matched controls (n = 47), with follow-up assessments at 90 days. Complementary experimental stroke studies were performed using transient and permanent middle cerebral artery occlusion (MCAo) in wild-type mice and in endothelial-specific RiboTag mice (Cdh5^Cre-ER(T)) that enable selective isolation of endothelial mRNA. In parallel, human brain microvascular endothelial cells were exposed to oxygen-glucose deprivation in vitro. Endothelial activation-related markers, expression of S1P-metabolizing enzymes and S1P receptors, BBB integrity, and circulating P-selectin levels were assessed by qPCR, Western blotting, immunohistochemistry, and ELISA-based approaches.

Results
Plasma S1P levels were significantly reduced in patients with acute ischemic stroke compared with controls and recovered at follow-up, consistent with findings in experimental stroke. Endothelial-specific transcriptomic profiling revealed reduced expression of sphingosine kinases, S1P-degrading enzymes, and S1P receptors (S1pr1, S1pr3, and S1pr4) in the ischemic brain endothelium. Lower vascular S1PR1 protein expression was associated with increased BBB disruption, and sphingosine kinase 2 protein abundance was reduced in small cerebral vessel endothelial cells of the lesioned compared to the contralateral hemisphere. These alterations were accompanied by acute changes in endothelial barrier- and activation-related markers, together with model-dependent changes in plasma P-selectin in mice. In patients, plasma P-selectin levels were not elevated acutely but showed an inverse association with plasma S1P concentrations.

Conclusions
Ischemic stroke associates with acute plasma S1P depletion that parallels altered brain-endothelial S1P pathway expression, signs of endothelial activation, and BBB disruption. These findings support plasma S1P as a candidate circulating marker associated with cerebrovascular injury after stroke. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Biological sciences, Molecular neuroscience, Neuroscience, Physiology
in
Fluids and Barriers of the CNS
volume
23
article number
82
publisher
BioMed Central (BMC)
external identifiers
  • pmid:42277837
  • scopus:105042325748
ISSN
2045-8118
DOI
10.1186/s12987-026-00828-z
language
English
LU publication?
yes
id
3bd5d740-0639-4fc6-b70f-c21717565f3a
date added to LUP
2026-08-10 16:48:02
date last changed
2026-08-11 08:24:43
@article{3bd5d740-0639-4fc6-b70f-c21717565f3a,
  abstract     = {{<b>Background</b><br/>Ischemic stroke remains a leading cause of disability and mortality worldwide, with limited acute therapeutic options. Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates endothelial function, vascular integrity, and immune responses, and reduced circulating S1P levels have been reported in ischemic stroke. Whether plasma S1P depletion parallels alterations in brain-endothelial S1P metabolism, receptor expression, and endothelial activation, however, remains unclear. Here, we characterized circulating S1P levels together with stroke-associated changes in brain-endothelial S1P pathway expression, markers related to endothelial activation, and blood-brain barrier (BBB) integrity.<br/><br/><b>Methods</b><br/>We quantified plasma S1P concentrations in patients with acute ischemic stroke (n = 50) and age- and sex-matched controls (n = 47), with follow-up assessments at 90 days. Complementary experimental stroke studies were performed using transient and permanent middle cerebral artery occlusion (MCAo) in wild-type mice and in endothelial-specific RiboTag mice (Cdh5^Cre-ER(T)) that enable selective isolation of endothelial mRNA. In parallel, human brain microvascular endothelial cells were exposed to oxygen-glucose deprivation in vitro. Endothelial activation-related markers, expression of S1P-metabolizing enzymes and S1P receptors, BBB integrity, and circulating P-selectin levels were assessed by qPCR, Western blotting, immunohistochemistry, and ELISA-based approaches.<br/><br/><b>Results</b><br/>Plasma S1P levels were significantly reduced in patients with acute ischemic stroke compared with controls and recovered at follow-up, consistent with findings in experimental stroke. Endothelial-specific transcriptomic profiling revealed reduced expression of sphingosine kinases, S1P-degrading enzymes, and S1P receptors (S1pr1, S1pr3, and S1pr4) in the ischemic brain endothelium. Lower vascular S1PR1 protein expression was associated with increased BBB disruption, and sphingosine kinase 2 protein abundance was reduced in small cerebral vessel endothelial cells of the lesioned compared to the contralateral hemisphere. These alterations were accompanied by acute changes in endothelial barrier- and activation-related markers, together with model-dependent changes in plasma P-selectin in mice. In patients, plasma P-selectin levels were not elevated acutely but showed an inverse association with plasma S1P concentrations.<br/><br/><b>Conclusions</b><br/>Ischemic stroke associates with acute plasma S1P depletion that parallels altered brain-endothelial S1P pathway expression, signs of endothelial activation, and BBB disruption. These findings support plasma S1P as a candidate circulating marker associated with cerebrovascular injury after stroke.}},
  author       = {{Porschen, Lisa Teresa and Matthes, Frank and Matuskova, Hana and Braadt, Lino and Petzold, Gabor C and Lindgren, Arne and Meissner, Anja}},
  issn         = {{2045-8118}},
  keywords     = {{Biological sciences; Molecular neuroscience; Neuroscience; Physiology}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Fluids and Barriers of the CNS}},
  title        = {{Circulating sphingosine-1-phosphate depletion is associated with endothelial activation and altered brain-endothelial S1P pathway expression in ischemic stroke}},
  url          = {{http://dx.doi.org/10.1186/s12987-026-00828-z}},
  doi          = {{10.1186/s12987-026-00828-z}},
  volume       = {{23}},
  year         = {{2026}},
}