Targeted role for sphingosine-1-phosphate receptor 1 in cerebrovascular integrity and inflammation during acute ischemic stroke

Abstract

Endothelial sphingosine-1-phosphate receptors are emerging as relevant therapeutic targets during acute ischemic stroke (AIS). Physiologically, the cerebrovascular endothelium plays a vital role in maintaining barrier integrity and cerebrovascular homeostasis. During a cerebral ischemic event, products from parenchymal cell death are released and trigger vascular endothelial dysfunction and vascular inflammation leading to barrier integrity disruption. Endothelial dysfunction, inflammation, and a breach in barrier property play a significant role in contributing to a vicious cycle which promotes brain edema formation and exacerbates neuronal injury post stroke. Data from experimental stroke models and clinical trials suggest that selective sphingosine-1-phosphate receptor type 1 (S1PR1) modulation improves endothelial health and function and, as a result, contributes to improved neurological outcome post ischemic injury. This review highlights the impact of sphingosine-1-phosphate (S1P)/S1PR1 signaling involved in blood brain barrier (BBB) integrity and cerebrovascular inflammation following AIS. We focus on the beneficial actions of S1PR1 signaling during ischemic injury including barrier protection to lessen brain edema formation and reduction in the development and progression of vascular inflammation by attenuating endothelial cell activation resulting in reduced neurovascular inflammation. Potential gaps and future directions related to the role of S1PR during AIS are also discussed.

Keywords: Acute ischemic stroke; Blood brain barrier integrity; Sphingosine-1 phosphate receptor; Vascular inflammation.