{"doi":"10.1101/2024.09.03.610974","title":"Novel Role of Endothelial CD45 in Regulating Endothelial-to-Mesenchymal Transition in Atherosclerosis","abstract":"ABSTRACT Background The protein tyrosine phosphatase CD45 is expressed in all nucleated cells of the hematopoietic system and in mitral valve endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndoMT). Our recent work indicated that activation of endogenous CD45 in human endothelial colony-forming cells (ECFCs) induced expression of multiple EndoMT marker genes. We hypothesized that CD45 may contribute to atherosclerosis; however, detailed molecular mechanisms underlying how CD45 may contribute to EndoMT and the impact of therapeutic manipulation of CD45 expression in atherosclerosis are unknown. Methods We generated a tamoxifen-inducible EC-specific CD45-deficient mouse strain (EC-iCD45KO) on an ApoE-deficient (WT/ApoE −/− ) background and fed them a Western diet (WD) to produce atherosclerosis. We enriched mouse aortic ECs with anti-CD31 beads to perform single-cell RNA sequencing. Cellular, biochemical and molecular approaches were used to investigate the effect of endothelial CD45-specific deletion on EndoMT and lesion development in an ApoE −/− mouse model of atherosclerosis. Results EC-iCD45KO mice showed reductions in lesion development, plaque macrophage infiltration, and expression of cell adhesion molecules when compared to WT/ApoE −/− controls. Single-cell RNA sequencing revealed that loss of endothelial CD45 decreases EndoMT marker expression and TGF-β signaling in atherosclerotic mice, which is associated with reduction of lesions. Mechanistically, CD45 loss increases Fibroblast Growth Factor Receptor 2 (FGFR2) expression in mouse aortic ECs and Krüppel-like Factor 2 (KLF2) expression in the aortic root. Endothelial CD45-deficiency also inhibits EndoMT and TGFβ signaling in atherosclerosis. Conclusions Our findings demonstrate that genetic depletion of endothelial CD45 protects against EndoMT-driven atherosclerosis by promoting FGFR2 and KLF2 expression while inhibiting Transforming Growth Factor beta (TGFβ) signaling and EndoMT. Consequently, targeting endothelial CD45 may represent a novel therapeutic strategy to reduce EndoMT in atherosclerosis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":491761,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"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":1087776,"name":"A. Kulandaisamy","orcid":"0000-0002-3367-2669","position":1,"is_corresponding":false},{"id":506679,"name":"Yao Wei Lu","orcid":"0000-0001-6200-2974","position":2,"is_corresponding":false},{"id":410113,"name":"Bo Zhu","orcid":"0000-0001-6043-8774","position":3,"is_corresponding":false},{"id":918196,"name":"Bandana Singh","orcid":"0000-0002-9599-118X","position":4,"is_corresponding":false},{"id":459573,"name":"Kui Cui","orcid":"0000-0003-2615-4932","position":5,"is_corresponding":false},{"id":459583,"name":"Jill Wylie‐Sears","orcid":"0000-0003-3305-8578","position":6,"is_corresponding":false},{"id":355674,"name":"Marina V. Malovichko","orcid":"0000-0003-2127-5858","position":7,"is_corresponding":false},{"id":459584,"name":"Scott W. Wong","orcid":"0000-0001-6855-0808","position":8,"is_corresponding":false},{"id":323348,"name":"Douglas B. Cowan","orcid":"0000-0002-6309-2737","position":9,"is_corresponding":false},{"id":364518,"name":"Masanori Aikawa","orcid":"0000-0002-9275-2079","position":10,"is_corresponding":false},{"id":1337277,"name":"Sanjay Srivastava","orcid":"0000-0002-1976-0398","position":11,"is_corresponding":false},{"id":238232,"name":"Da‐Zhi Wang","orcid":"0000-0003-1774-6549","position":12,"is_corresponding":false},{"id":381507,"name":"Joyce Bischoff","orcid":"0000-0002-6367-1974","position":13,"is_corresponding":false},{"id":316744,"name":"Kaifu Chen","orcid":"0000-0003-1009-4357","position":14,"is_corresponding":false},{"id":1337278,"name":"Hong Chen","orcid":"0000-0003-0082-2939","position":15,"is_corresponding":false},{"id":489898,"name":"Qianman Peng","orcid":"0000-0003-1854-0710","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:08:45.247225Z","pmid":"39282400","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":[]}