The selective sphingosine 1-phosphate receptor 1 modulator RP101075 improves microvascular circulation after cerebrovascular thrombosis.

Abstract

Sphingosine-1-phosphate receptor (S1PR) modulators provide protection in preclinical and clinical studies for ischemic stroke, but the influences of S1PR modulation on microvascular thrombosis remain poorly understood. This study investigates the impact of a selective S1PR1 modulator RP101075 on microvascular circulation in a mouse model of laser-induced thrombosis. The flow velocity of cortical arterioles in mice was measured in vivo under 2-photon laser scanning microscopy. Thrombosis was induced in cortical arterioles by laser irritation. At 30 min after laser-induced thrombosis, mice were treated with either RP101075 or vehicle. RP101075 did not alter the flow velocity of cortical arterioles under physiologic conditions. Laser-induced thrombosis led to a pronounced reduction of flow velocity in cortical arterioles that persisted for ≥90 min. The reduction of flow velocity in cortical arterioles following thrombosis was significantly attenuated following RP101075 treatment. RP101075 did not significantly affect coagulation time, bleeding time, heart rate, and blood pressure. In addition, RP101075 treatment reduced thrombus volume, which was accompanied by a reduction of leukocyte content in the thrombus. Our findings demonstrate that the selective S1PR1 modulator RP101075 improves microvascular circulation after thrombosis, implying a component of improved microvascular circulation to the benefit of S1PR modulation in cerebral ischemia.-Li, H., Zhou, X., Li, Y., Ma, X., Gonzales, R. J., Qiu, S., Shi, F.-D., Liu, Q. The selective sphingosine 1-phosphate receptor 1 modulator RP101075 improves microvascular circulation after cerebrovascular thrombosis.