{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T07:50:20Z","timestamp":1782805820700,"version":"3.54.5"},"reference-count":41,"publisher":"American Physiological Society","issue":"5","license":[{"start":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T00:00:00Z","timestamp":1753488000000},"content-version":"vor","delay-in-days":206,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL-120867"],"award-info":[{"award-number":["R01 HL-120867"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL-122578"],"award-info":[{"award-number":["HL-122578"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00-HL141143"],"award-info":[{"award-number":["R00-HL141143"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The proper functioning of lymphatic valves is critical for unidirectional lymph transport. Valve development and maintenance depends on multiple genes in lymphatic endothelium, including those controlling the expression of 4 connexin (Cx) isoforms\u2014Cx37, Cx47, Cx43, and Cx45. The relative importance of these isoforms for valve function is undefined, but primary human lymphedema is linked to loss-of-function mutations in Cx47 or Cx43, while deficiencies in Cx43 or Cx45 produce functional valve defects in mice. Tests of back leak and closure for single lymphatic valves from mice with selective deficiency of each Cx isoform revealed defects associated with the loss of Cx37 or Cx43, but not Cx47. Combined deletion of multiple isoforms, including Cx45 but not Cx47, produced even more severe valve defects in certain genotypes, sometimes with nearly complete regression of valves within 6 d. Back leak across connexin-deficient LVs correlated highly with gaps between the commissures formed by leaflet insertion into the vessel wall, indicating that connexin function may be critical for the formation and\/or maintenance of leaflet commissures. Our results reveal the following hierarchy of Cx importance in valve function: Cx37\u00a0=\u00a0Cx43\u00a0&amp;gt;\u00a0Cx45\u00a0&amp;gt;\u00a0Cx47 and predict that patients with loss of function mutations in Cx37 (GJA4) should develop lymphedema. We propose a general classification scheme describing 4 stages of progressive valve dysfunction.<\/jats:p>","DOI":"10.1093\/function\/zqaf034","type":"journal-article","created":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T11:47:27Z","timestamp":1753530447000},"source":"Crossref","is-referenced-by-count":7,"title":["Hierarchical Requirement for Endothelial Cell Connexins Cx37, Cx47, Cx43, and Cx45 in Lymphatic Valve Function"],"prefix":"10.1152","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7992-9300","authenticated-orcid":false,"given":"Michael J","family":"Davis","sequence":"first","affiliation":[{"name":"University of Missouri Department of Medical Pharmacology & Physiology, , Columbia, MO 65212 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge A","family":"Castorena-Gonzalez","sequence":"additional","affiliation":[{"name":"Tulane University School of Medicine Department of Pharmacology, , New Orleans, LA 70112 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"University of Missouri Department of Medical Pharmacology & Physiology, , Columbia, MO 65212 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M","family":"Simon","sequence":"additional","affiliation":[{"name":"University of Arizona School of Medicine Department of Physiology, , Tucson, AZ 85724 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R Sathish","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation Cardiovascular Biology Research Program, , Oklahoma City, OK 73104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","published-online":{"date-parts":[[2025,7,26]]},"reference":[{"key":"2025091915585733400_bib1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.addr.2020.12.005","article-title":"Development and aging of the lymphatic vascular system","volume":"169","author":"Gonzalez-Loyola","year":"2021","journal-title":"Adv Drug Deliv Rev"},{"issue":"10","key":"2025091915585733400_bib2","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ng1642","article-title":"Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity","volume":"37","author":"Harvey","year":"2005","journal-title":"Nat Genet"},{"issue":"9","key":"2025091915585733400_bib3","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1038\/nm1094","article-title":"Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis","volume":"10","author":"Petrova","year":"2004","journal-title":"Nat Med"},{"issue":"2","key":"2025091915585733400_bib4","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.devcel.2011.12.020","article-title":"Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation","volume":"22","author":"Sabine","year":"2012","journal-title":"Dev Cell"},{"issue":"4","key":"2025091915585733400_bib5","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/cge.12158","article-title":"A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family","volume":"84","author":"Brice","year":"2013","journal-title":"Clin Genet"},{"issue":"6","key":"2025091915585733400_bib6","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.ajhg.2010.04.010","article-title":"GJC2 missense mutations cause human lymphedema","volume":"86","author":"Ferrell","year":"2010","journal-title":"Am Hum Genet"},{"issue":"8","key":"2025091915585733400_bib7","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1158\/1078-0432.CCR-11-2303","article-title":"Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment","volume":"18","author":"Finegold","year":"2012","journal-title":"Clin Cancer Res"},{"issue":"6","key":"2025091915585733400_bib8","first-page":"541","article-title":"Diagnosis and treatment of primary lymphedema. 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