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Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth
and Protects against Subsequent Stroke
#MMPMID26367258
Ichijo M
; Ishibashi S
; Li F
; Yui D
; Miki K
; Mizusawa H
; Yokota T
PLoS One
2015[]; 10
(9
): e0138029
PMID26367258
show ga
BACKGROUND AND PURPOSE: Collateral growth after acute occlusion of an
intracranial artery is triggered by increasing shear stress in preexisting
collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1) on
endothelial cells was reported to be essential in sensing fluid shear stress.
Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and
investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral
growth and subsequent ischemic damage after focal ischemia. METHODS: In C57Bl/6
mice (n = 133) subjected to unilateral common carotid occlusion (CCAO) and sham
surgery. The first series examined the time course of collateral growth, cell
proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO.
The second series examined the relationship between pharmacological regulation of
S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly
assigned to one of the following groups: LtCCAO and daily intraperitoneal (i.p.)
injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day); sham
surgery and daily i.p. injection for 7 days of SEW2871 after surgery; LtCCAO and
daily i.p. injection for 7 days of SEW2871 and an S1PR1 inverse agonist
(VPC23019, 0.5 mg/kg); LtCCAO and daily i.p. injection of DMSO for 7 days after
surgery; and sham surgery and daily i.p. injection of DMSO for 7 days.
Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex
perfusion method, and a set of animals underwent subsequent permanent middle
cerebral artery occlusion (pMCAO) 7 days after the treatment termination.
Neurological functions 1 hour, 1, 4, and 7 days and infarction volume 7 days
after pMCAO were evaluated. RESULTS: In parallel with the increase in S1PR1 mRNA
levels, S1PR1 expression colocalized with endothelial cell markers in the
leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7
days after CCAO. Mitotic cell numbers in the leptomeningeal arteries increased
after CCAO. Administration of the S1PR1 selective agonist significantly increased
cerebral blood flow (CBF) and the diameter of leptomeningeal collateral vessels
(42.9 ± 2.6 ?m) compared with the controls (27.6 ± 5.7 ?m; P < 0.01). S1PR1
inverse agonist administration diminished the effect of the S1PR1 agonist (P <
0.001). After pMCAO, S1PR1 agonist pretreated animals showed significantly
smaller infarct volume (17.5% ± 4.0% vs. 7.7% ± 4.0%, P < 0.01) and better
functional recovery than vehicle-treated controls. CONCLUSIONS: These results
suggest that S1PR1 is one of the principal regulators of leptomeningeal
collateral recruitment at the site of increased shear stress and provide evidence
that an S1PR1 selective agonist has a role in promoting collateral growth and
preventing of ischemic damage and neurological dysfunction after subsequent
stroke in patients with intracranial major artery stenosis or occlusion.
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