{"doi":"10.14336/ad.2024.0098","title":"Progressive Disruption of Sphingosine-1-Phosphate Receptor 1 Correlates with Blood-Brain Barrier Leakage in A Rat Model of Chronic Hypoxic Hypoperfusion","abstract":"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 (S1PR<sub>1</sub>) on endothelial cells. This study tested the hypothesis that hypoxic hypoperfusion triggers capillary endothelial S1PR<sub>1</sub> 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 S1PR<sub>1</sub> agonist SEW2871 was used to activate S1PR<sub>1</sub>. Significant progressive reduction of S1PR<sub>1</sub> was detected in rat brains from 4 to 9 weeks following UCAO/JPD onset, which was also detected in cerebral vasculature in human SVD. S1PR<sub>1</sub> activation by SEW2871 significantly reduced lesions in both white and grey matter and ameliorated cerebral blood flow. SEW2871 reversed the loss of endothelial S1PR<sub>1</sub> 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 S1PR<sub>2</sub>/Erk1/2 activation. Our data suggest S1PR<sub>1</sub> 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 S1PR<sub>1</sub> signalling likely reveals a novel therapeutic target for SVD.","journal":"Aging and Disease","year":2024,"id":459576,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":476767,"name":"Yirong Yang","orcid":"0000-0003-2252-0245","position":1,"is_corresponding":false},{"id":769790,"name":"Kelsey Duval","orcid":null,"position":2,"is_corresponding":false},{"id":1286681,"name":"Michael Griego","orcid":"0000-0003-2127-3342","position":3,"is_corresponding":false},{"id":1286682,"name":"Haojie Chen","orcid":"0009-0006-1034-2962","position":4,"is_corresponding":false},{"id":1073370,"name":"Karen S. SantaCruz","orcid":null,"position":5,"is_corresponding":false},{"id":1287134,"name":"Haoran Deng","orcid":null,"position":6,"is_corresponding":false},{"id":1286683,"name":"Carlos Pérez","orcid":"0000-0001-8425-1875","position":7,"is_corresponding":false},{"id":1287135,"name":"Sean Maez","orcid":null,"position":8,"is_corresponding":false},{"id":689986,"name":"Sasha Hobson","orcid":null,"position":9,"is_corresponding":false},{"id":1287136,"name":"Theodore Li","orcid":null,"position":10,"is_corresponding":false},{"id":1286684,"name":"Halima Akter","orcid":"0000-0002-4683-4225","position":11,"is_corresponding":false},{"id":669861,"name":"Michel Torbey","orcid":"0000-0001-8187-9683","position":12,"is_corresponding":false},{"id":322530,"name":"Yi Yang","orcid":"0000-0003-1493-2952","position":13,"is_corresponding":false},{"id":769140,"name":"Jeffrey Thompson","orcid":"0000-0002-4012-5698","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-19T02:03:59.428859Z","pmid":"38916732","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}