{"doi":"10.1002/advs.202505342","title":"Tie2‐Dependent Mechanisms Influence Leptomeningeal Collateral Dynamics and Reperfusion Following Stroke","abstract":"Leptomeningeal collateral vessels help redistribute cerebral blood flow following arterial obstruction, reducing tissue damage. This study investigates the Tie2 receptor peptide agonist Vasculotide in a permanent middle cerebral artery occlusion (pMCAO) model. Vasculotide enhanced early diameter enlargement of pre-existing pial collaterals, which may be mediated by structural remodeling, as evidenced by endothelial proliferation. These changes correlated with reduced infarct volume, blood-brain barrier disruption, enhanced blood flow, and functional recovery at 3-28 days post-pMCAO. Conditional endothelial cell (EC)-specific EphA4 knockout (KO) mice exhibited increased Tie2 and Ang-1 expression, mimicking the effects of Vasculotide on collateral size. Simultaneous genetic loss of EC-specific EphA4 and Tie2 attenuated these outcomes. Nitric oxide inhibition partially blocked collateral enlargement in EC-KO mice, suggesting the presence of additional contributors. Bulk RNAseq of meningeal tissue revealed upregulation of Krt5, Krt14, and Col17a1 in the ipsilateral meninges of Vasculotide-treated and EC-specific EphA4 KO mice. Notably, the number of Krt5-expressing cells is increased on the leptomeningeal arterial vasculature of KO mice, suggesting a novel contribution to collateral enlargement. The opposing roles of EphA4 and Tie2 in collateral dynamics are demonstrated, and a novel molecular program is identified that can be targeted to enhance their diameter enlargement in ischemic stroke.","journal":"Advanced Science","year":2025,"id":579503,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"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":875106,"name":"Caroline de Jager","orcid":"0000-0003-2714-5886","position":1,"is_corresponding":false},{"id":1490092,"name":"Kennedie Lyles","orcid":null,"position":2,"is_corresponding":false},{"id":539744,"name":"Nathalie Groot","orcid":"0000-0002-5389-631X","position":3,"is_corresponding":false},{"id":1490093,"name":"Jackie Zhu","orcid":null,"position":4,"is_corresponding":false},{"id":1489681,"name":"Yu‐Hui Lin","orcid":"0000-0003-2244-0587","position":5,"is_corresponding":false},{"id":882117,"name":"Michael Chen","orcid":"0000-0003-1855-7897","position":6,"is_corresponding":false},{"id":772596,"name":"Hehuang Xie","orcid":"0000-0001-5739-1653","position":7,"is_corresponding":false},{"id":304541,"name":"John B. Matson","orcid":"0000-0001-7984-5396","position":8,"is_corresponding":false},{"id":234777,"name":"Michelle H. Theus","orcid":"0000-0001-6485-2104","position":9,"is_corresponding":false},{"id":411746,"name":"Alexandra M. Kaloss","orcid":"0000-0002-2054-2320","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T02:58:30.282164Z","pmid":"41164967","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":[]}