# Sphingosine 1 phosphate signaling in cerebral small vessel disease

> **NIH NIH RF1** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $2,640,472

## Abstract

Project Summary / Abstract
 Cerebral Small Vessel Disease (SVD) is a vascular disorder that contributes to approximately 50% of
human dementias world-wide. Once initiated, SVD proceeds ineluctably towards its conclusion. Preventing the
onset or progression of cerebrovascular dysfunction is hampered by our lack of knowledge of the molecular and
cellular mechanisms that underlie basic vascular pathobiology. SVD is caused by hypoxic hypoperfusion that
underlies the etiology and is characterized by progressive white matter lesions (WML) in the brain’s subcortical
structures. Human studies indicated that blood-brain barrier (BBB) dysfunction plays a causative role in SVD
pathology and is likely the link between hypoxic hypoperfusion and the WML. Hence, we ask whether reversal
of BBB damage will be accompanied by an improvement in the progression of SVD pathology, and how this
reversal could be accomplished. Sphingosine 1 phosphate (S1P), a signaling sphingolipid, is a key regulator of
BBB function through binding to its receptors (S1PR1-5). Activation of S1PR1 by S1P promotes vascular
maturation, stabilization and assembly of endothelial tight junctions (TJs) and adherens junctions (AJs), reduces
BBB leakage, and limits leukocyte infiltration. Reversal of BBB dysfunction in SVD may be possible by targeting
the S1PR1 pathway, however, its effect on BBB dysfunction in SVD and other vascular dementias has not been
examined. The objective of this proposal is to determine if agonist-induced activation of S1PR1 will reverse
hypoxic hypoperfusion-induced BBB disruption, reduce inflammation, and ameliorate WML formation and
cognitive deficits. Our central hypothesis is that chronic hypoxic hypoperfusion downregulates capillary
endothelial S1PR1, disrupting endothelial TJs/AJs, leading to BBB dysfunction and neuroinflammation. We will
test our hypothesis in a spontaneously hypertensive rat-stroke prone (SHRSP) model. Our published studies
documented the hypoxia with electron paramagnetic resonance, the WML and BBB damage with serial MRIs,
and the cognitive impairment in the SHRSPs, similar to those in SVD when the SHRSPs are subjected to
Japanese Permissive Diet (JPD) and unilateral carotid occlusion (UCAO). Aim 1 is to determine whether S1PR1
activation by the selective agonist SEW2871 will preserve BBB permeability. Aim 2 is to determine whether
S1PR1 activation will enhance endothelial cell junctions and limit immune cell infiltration. Aim 3 is to determine
whether S1PR1 activation enhances BBB integrity by reducing EC apoptosis, as well as by promoting EC
proliferation, cytoskeletal reorganization, and angiogenesis. The premise for this proposal focuses on, for the
first time, on unraveling the novel mechanisms involving the S1P-S1PR axis as a means to prevent progressive
neurodegeneration and cognitive deficits in SVD through the reversal of BBB disruption. Using a unique model
and innovative approaches, the proposed work aims to fill significant gaps in ...

## Key facts

- **NIH application ID:** 9972630
- **Project number:** 1RF1NS110724-01A1
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Yi Yang
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,640,472
- **Award type:** 1
- **Project period:** 2020-04-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972630

## Citation

> US National Institutes of Health, RePORTER application 9972630, Sphingosine 1 phosphate signaling in cerebral small vessel disease (1RF1NS110724-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972630. Licensed CC0.

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