Progressive Disruption of Sphingosine-1-Phosphate Receptor 1 Correlates with Blood-Brain Barrier Leakage in A Rat Model of Chronic Hypoxic Hypoperfusion

Endothelial dysfunction and blood-brain barrier (BBB) leakage have been suggested as a fundamental role in the development of cerebral small vessel disease (SVD) pathology. However, the molecular and cellular mechanisms that link cerebral hypoxic hypoperfusion and BBB disruption remain elusive. Sphingosine-1-phosphate (S1P) regulates the BBB integrity by binding to its receptor isoform 1 (S1PR₁) on endothelial cells. This study tested the hypothesis that hypoxic hypoperfusion triggers capillary endothelial S1PR₁ disruption, which compromises BBB integrity and leads to SVD-related neuropathological changes, using a chronic hypoxic hypoperfusion model with BBB dysfunction. Spontaneously hypertensive rat stroke-prone underwent unilateral carotid artery occlusion (UCAO) followed by a Japanese permissive diet (JPD) for up to 9 weeks. Selective S1PR₁ agonist SEW2871 was used to activate S1PR₁. Significant progressive reduction of S1PR₁ was detected in rat brains from 4 to 9 weeks following UCAO/JPD onset, which was also detected in cerebral vasculature in human SVD. S1PR₁ activation by SEW2871 significantly reduced lesions in both white and grey matter and ameliorated cerebral blood flow. SEW2871 reversed the loss of endothelial S1PR₁ and tight junction proteins, and significantly attenuated UCAO/JPD induced accumulation of neuronal phosphorylated tau. This protective role of SEW2871 is associated with promotion of Akt phosphorylation and inhibition of S1PR₂/Erk1/2 activation. Our data suggest S1PR₁ signalling as a potential molecular mechanistic basis that links hypoxic hypoperfusion with BBB damage in the neuropathological cascades in SVD. The reversal of BBB disruption through pharmacological intervention of S1PR₁ signalling likely reveals a novel therapeutic target for SVD.