{"doi":"10.1111/micc.70035","title":"<scp>AP</scp> ‐1 Is an Initial Convergent Transcriptional Response in Lymphatic Endothelium to <scp>VEGF</scp> ‐C or <scp>TNFα</scp>","abstract":"OBJECTIVE: The lymphatic vasculature plays a central role in resolving inflammation by draining interstitial fluid, immune cells, and inflammatory mediators. While vascular endothelial growth factor C (VEGF-C) is a well-established driver of lymphangiogenesis, the effects of chronic pro-inflammatory cytokines on lymphatic remodeling remain incompletely defined. METHODS: Here, we investigated how tumor necrosis factor alpha (TNFα) compares with VEGF-C in regulating lymphatic endothelial structure and function using human dermal lymphatic endothelial cells (HDLECs). RESULTS: In tube formation and spheroid sprouting assays, both VEGF-C and TNFα supported early lymphangiogenic events, promoting robust sprouting and network development within 24 h. However, when pre-formed microvascular networks were challenged, prolonged TNFα exposure triggered progressive destabilization, characterized by tube fragmentation, reduced proliferation, and impaired metabolic activity, whereas VEGF-C preserved network stability. Mechanistically, both VEGF-C and TNFα induced rapid phosphorylation of p38 MAPK and upregulation of Activator Protein-1 (AP-1) transcription factor subunits within 30 min, suggesting a convergent early transcriptional response. Bulk RNA-sequencing confirmed shared induction of AP-1 family genes (FOS, JUN, ATF), highlighting AP-1 as a candidate regulator of the transition between adaptive and maladaptive outcomes. We propose that transient AP-1 activation promotes pro-lymphangiogenic programs, while sustained TNFα signaling redirects AP-1 activity toward stress, growth arrest, and apoptosis, leading to lymphatic regression. CONCLUSION: These findings identify TNFα as a temporally bifunctional regulator of lymphatic endothelial fate.","journal":"Microcirculation","year":2025,"id":583277,"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":0.924,"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":1112714,"name":"Zuzanna J. Juśkiewicz","orcid":"0009-0006-2612-2665","position":1,"is_corresponding":false},{"id":190934,"name":"Brant E. Isakson","orcid":"0000-0002-7692-6294","position":2,"is_corresponding":false},{"id":1495882,"name":"Ewa A. Kreft","orcid":null,"position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:59:03.725721Z","pmid":"41277348","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":[]}