Sphingosine-1-Phosphate Receptor 1 Activation Enhances Leptomeningeal Collateral Development and Improves Outcome after Stroke in Mice

Development of collateral circulation after acute ischemic stroke is triggered by shear stress that occurs in pre-existing arterioles. Recently, sphingosine-1-phosphate receptor 1 (S1P1) on endothelial cells was reported to sense shear stress and transduce its signaling pathways. BALB/c mice (n = 118) were subjected to permanent middle cerebral artery occlusion (pMCAO) or sham operation. We investigated the effect of an S1P1-selective agonist SEW2871 on leptomeningeal collateral arteries and neurological outcome after pMCAO. Immunohistochemistry showed that without treatment, the expression of S1P1 on endothelial cells of leptomeningeal arteries and capillaries increased early after pMCAO, peaking at 6 hours, whereas a significant increase in the expression of S1P1 in neurons was seen from 24 hours later. After intraperitoneal administration of SEW2871 for 7 days after pMCAO, the number of leptomeningeal collateral arteries was significantly increased, cerebral blood flow improved, infarct volume was decreased, and neurological outcome improved compared with the controls. Significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS) as early as 6 hours after pMCAO and higher expression of tight junction proteins at postoperative day 3 were observed with SEW2871 treatment as assessed by Western blot. Daily administration of SEW2871 also increased capillary density in peri-infarct regions and promoted monocyte/macrophage mobilization to the surface of ischemic cortex at 7 days after pMCAO. An S1P1-selective agonist enhanced leptomeningeal collateral circulation via eNOS phosphorylation and promoted postischemic angiogenesis with reinforced blood–brain barrier integrity in a mouse model of acute ischemic stroke, leading to smaller infarct volume and better neurological outcome.