{"doi":"10.1111/bpa.70037","title":"Nitro‐oleic acid activation of endothelial <scp>PPARγ</scp> signaling pathway alleviates neurovascular injury and improves functional outcomes in ischemic stroke","abstract":"Abstract Nitro‐oleic acid (OA‐NO 2 ) is an endogenous peroxisome proliferator‐activated receptor‐γ (PPARγ) ligand and can activate this receptor under both physiological and pathological conditions. In this study, we explore the role and molecular mechanisms of OA‐NO 2 in maintaining blood–brain barrier (BBB) integrity and enhancing neurovascular function during ischemic stroke, with a particular emphasis on the activation of endothelial PPARγ signaling pathways. Endothelial cell‐selective PPARγ conditional knockout (EC‐PPARγ cKO) and wild‐type (WT) mice underwent 1 h middle cerebral artery occlusion (MCAO) with 1–7 days of reperfusion. Mice were treated with oleic acid (OA) or OA‐NO 2 (5 mg/kg) via tail vein 2 h after MCAO. Neurobehavioral deficits were assessed on days 3, 5, and 7 after MCAO. Neuroinflammation and BBB function were assessed on days 1 or 2 after MCAO by immunohistochemistry, RT‐qPCR, or Western blot analysis. Compared to OA controls, intravenous administration of OA‐NO 2 led to reduced BBB leakage in ischemic brains, as indicated by a significant decrease in the extravasation of BBB tracers. This reduction in BBB leakage was also almost abolished in the EC‐PPARγ cKO mice. Furthermore, OA‐NO 2 treatment reduced brain infarction in stroke mice, but this protective effect was completely reversed in the EC‐PPARγ cKO mice. Interestingly, OA‐NO 2 treatment promoted a shift towards an anti‐inflammatory microglial phenotype (M2) in the peri‐infarct regions of WT mice, but not in EC‐PPARγ cKO mice. Mechanistically, OA‐NO 2 increased levels of major endothelial tight junction proteins in WT mice but not in EC‐PPARγ cKO mice following ischemic stroke. These findings suggest that OA‐NO 2 activation of endothelial PPARγ signaling cascade attenuates neurovascular injury after ischemic stroke.","journal":"Brain Pathology","year":2025,"id":526636,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1062525,"name":"Na Qiu","orcid":"0009-0005-5594-2892","position":1,"is_corresponding":false},{"id":1063106,"name":"Andrew Ni","orcid":null,"position":2,"is_corresponding":false},{"id":1402191,"name":"Xiaotao Xu","orcid":"0000-0002-0520-4008","position":3,"is_corresponding":false},{"id":319921,"name":"Ping Sun","orcid":"0000-0001-6307-3723","position":4,"is_corresponding":false},{"id":240579,"name":"Shun Li","orcid":"0000-0001-8601-2261","position":5,"is_corresponding":false},{"id":319923,"name":"Ke‐Jie Yin","orcid":"0000-0002-7169-3858","position":6,"is_corresponding":false},{"id":1265907,"name":"Tianqing Xiong","orcid":"0000-0001-6497-7847","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:50:30.402772Z","pmid":"40847618","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":[]}