Differential S1PR Expression and Altered Barrier, and Inflammatory Marker Levels in Human Brain Endothelial Cells Following Acute Ischemia-Reperfusion Like Injury

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ABSTRACT There are five known sphingosine-1-phosphate receptor (S1PR) types, and each type is coupled to diverse heterotrimeric G-protein subunits. S1PR type 1 (S1PR1) is highly expressed in the endothelium and receptor signaling pathways beneficially impact barrier function, thus there is a growing interest in the potential therapeutic role of S1PR1 during acute stroke injury. However, assessment of cerebrovascular S1PR1 and other S1PR expression profiles following acute ischemia-reperfusion injury have not yet been investigated. Therefore, we assessed the expression profile of human brain microvascular endothelial (HBMEC) S1PR1-5 following hypoxia plus glucose deprivation (HGD) exposure and HGD with reperfusion (HGD/R). We also investigated endothelial tight junction barrier and inflammatory mediator expression, indicative of an activated endothelial phenotype post HGD or HGD/R. Additionally, we investigated the effect of IL-1β, a downstream HGD induced inflammatory mediator, on endothelial mRNA expression of markers of function, barrier integrity, and inflammation and determined whether selective S1PR1 agonism altered mRNA expression of these genes. In terms of S1PR expression, a differential mRNA expression profile was observed revealing prominent basal endothelial expression of S1PR1-3. Following HGD, S1PR1 mRNA and protein expression increased with no observed changes in S1PR2 or S1PR3 protein levels. HGD/R increased endothelial inflammatory mediator and occludin mRNA expression with a temporal-dependent decrease in endothelial S1PR1 and claudin-5. Interestingly, we observed a positive and negative correlation between S1PR1 and S1PR2/3 with claudin-5, respectively. Selective S1PR1 agonism attenuated IL-1β induced MMP-9 mRNA and activity. In conclusion, HGD/R acutely increases endothelial cell expression of S1PR1 which presents a potential therapeutic target within the cerebrovasculature following ischemia-reperfusion injury. Additionally, HGD/R may potentially induce a phenotypic transformation within HBMECs, in which occludin expression predominates over claudin-5. NEW & NOTEWORTHY Abstract Figure Graphical Abstract

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