Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth and Protects against Subsequent Stroke

Abstract

Background and PurposeCollateral 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.MethodsIn 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 (ip) injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day); sham surgery and daily ip injection for 7 days of SEW2871 after surgery; LtCCAO and daily ip injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg); LtCCAO and daily ip injection of DMSO for 7 days after surgery; and sham surgery and daily ip 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) 7days after the treatment termination. Neurological functions 1hour, 1, 4, and 7days and infarction volume 7days after pMCAO were evaluated.ResultsIn 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 μm) compared with the controls (27.6 ± 5.7 μm; 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.ConclusionsThese 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.

Adipose tissue, metabolic and inflammatory responses to stroke are altered in obese mice

“…Two specific metabolite or metabolite classes that require further investigation are sphinganine-1-phosphate (4-fold higher in naïve ob/ob mice) metabolites and the metabolite class of plasmalogens. The sphinganine-1-phosphate-related metabolite sphingosine-1-phosphate has been implicated in poor outcome for ischemic stroke ( Ichijo et al, 2015 ; Maceyka et al, 2013 ; Moon et al, 2015 ) and sphingolipid metabolism before and after stroke is therefore worthy of investigation. Plasmalogens are identifiable by their ether linkage at the sn-1 position, and can make up 20% of all glycerophosphocholines in the brain ( Farooqui and Horrocks, 2001 ).…”

Time course of collateral vessel formation after retinal vein occlusion visualized by OCTA and elucidation of factors in their formation

“…Results showed that the amount of S1PR1 mRNA peaked at 6 h after blood vessel occlusion, and this was significantly higher than in control mice. Similarly, in a previous report utilizing a mouse cerebral infarction model, Ichijo described that the S1PR1 mRNA levels peaked 7 days after blood vessel occlusion [ 22 ]. We also investigated the immunohistochemical co-staining of CD31 and S1PR1 in retinal flat mounts.…”

“…Ichijo and Iwasawa et al. described how shear stress applied to occluded blood vessels led to the formation of collateral vessels in their experimental cerebral infarction model [ 15 , 22 , 23 ]. Similarly, Lloyd et al.…”

Enhanced Phospholipase A2 Group 3 Expression by Oxidative Stress Decreases the Insulin-Degrading Enzyme

“…Wild-type and Ttpa -/- mice were fed on a normal (36 mg of α-tocopherol/kg), α-tocopherol-supplemented (600 mg of α-tocopherol/kg), or α-tocopherol-deficient diet until the time of use. For the ischemic mouse model, male C57Bl/6 (18 weeks old) mice were used for the surgical procedure for left permanent middle cerebral artery occlusion [ 20 ] and used for the histological examinations on day 7 after surgery. For the traumatic brain injury model, postnatal day 2 (P2) mice were subjected to cryogenic injury as described previously [ 21 ].…”