{"doi":"10.1073/pnas.2308941120","title":"A 3D biomimetic model of lymphatics reveals cell–cell junction tightening and lymphedema via a cytokine-induced ROCK2/JAM-A complex","abstract":"Impaired lymphatic drainage and lymphedema are major morbidities whose mechanisms have remained obscure. To study lymphatic drainage and its impairment, we engineered a microfluidic culture model of lymphatic vessels draining interstitial fluid. This lymphatic drainage-on-chip revealed that inflammatory cytokines that are known to disrupt blood vessel junctions instead tightened lymphatic cell-cell junctions and impeded lymphatic drainage. This opposing response was further demonstrated when inhibition of rho-associated protein kinase (ROCK) was found to normalize fluid drainage under cytokine challenge by simultaneously loosening lymphatic junctions and tightening blood vessel junctions. Studies also revealed a previously undescribed shift in ROCK isoforms in lymphatic endothelial cells, wherein a ROCK2/junctional adhesion molecule-A (JAM-A) complex emerges that is responsible for the cytokine-induced lymphatic junction zippering. To validate these in vitro findings, we further demonstrated in a genetic mouse model that lymphatic-specific knockout of ROCK2 reversed lymphedema in vivo. These studies provide a unique platform to generate interstitial fluid pressure and measure the drainage of interstitial fluid into lymphatics and reveal a previously unappreciated ROCK2-mediated mechanism in regulating lymphatic drainage.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":329029,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":504621,"name":"Siu‐Lung Chan","orcid":"0000-0001-7564-3287","position":1,"is_corresponding":false},{"id":410112,"name":"Yang Lee","orcid":"0000-0002-8040-3648","position":2,"is_corresponding":false},{"id":282749,"name":"William J. Polacheck","orcid":"0000-0003-2728-0746","position":3,"is_corresponding":false},{"id":1051599,"name":"Sukyoung Kwak","orcid":null,"position":4,"is_corresponding":false},{"id":460439,"name":"Aiyun Wen","orcid":null,"position":5,"is_corresponding":false},{"id":109225,"name":"Duc-Huy T. Nguyen","orcid":"0000-0003-0805-8103","position":6,"is_corresponding":false},{"id":323196,"name":"Matthew L. Kutys","orcid":"0000-0002-0752-649X","position":7,"is_corresponding":false},{"id":715143,"name":"Stella Alimperti","orcid":"0000-0002-7954-5737","position":8,"is_corresponding":false},{"id":796612,"name":"Anna M. Kolarzyk","orcid":null,"position":9,"is_corresponding":false},{"id":1051078,"name":"Tae Joon Kwak","orcid":"0000-0003-1669-1996","position":10,"is_corresponding":false},{"id":302137,"name":"Jeroen Eyckmans","orcid":"0000-0003-1475-8149","position":11,"is_corresponding":false},{"id":474667,"name":"Diane R. Bielenberg","orcid":"0000-0003-3905-0059","position":12,"is_corresponding":false},{"id":410115,"name":"Hong Chen","orcid":"0000-0002-1906-6611","position":13,"is_corresponding":false},{"id":232957,"name":"Christopher S. Chen","orcid":"0000-0003-2445-8449","position":14,"is_corresponding":false},{"id":796141,"name":"Esak Lee","orcid":"0000-0002-5328-6677","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:08:56.940647Z","pmid":"37782785","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":[]}