{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:29:06Z","timestamp":1790393346707,"version":"4.1.0"},"reference-count":56,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["BHF RG\/F\/20\/110025"],"award-info":[{"award-number":["BHF RG\/F\/20\/110025"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council","award":["MR\/W028379\/1"],"award-info":[{"award-number":["MR\/W028379\/1"]}]},{"DOI":"10.13039\/501100005617","name":"BHF Centre of Research Excellence, Oxford","doi-asserted-by":"crossref","award":["RE\/13\/1\/30181"],"award-info":[{"award-number":["RE\/13\/1\/30181"]}],"id":[{"id":"10.13039\/501100005617","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100014013","name":"UKRI","doi-asserted-by":"crossref","award":["523"],"award-info":[{"award-number":["523"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:p>\n                    Lymphatic valves are essential for maintaining tissue fluid homeostasis, and their dysfunction leads to lymphedema, a morbid and disfiguring disease without a cure. Mechanical forces due to lymph flow are required for proper lymphatic valve development, yet it remains unclear how lymphatic endothelial cells (LECs) sense and decode mechanical signals. In this study, we identify the cell guidance semaphorin receptor plexin D1 (PLXND1) as a lymphatic mechanosensor required for lymphatic valve morphogenesis. Conditional genetic ablation of\n                    <jats:italic>Plxnd1<\/jats:italic>\n                    in LECs caused major defects in lymphatic valve development in 2 different lymphatic vascular beds. Mechanistically, PLXND1 acted as a mechanosensor within a lymphatic mechanocomplex, initiating distinct mechanical signals and activating the lymphatic valve transcriptional program through an unconventional pathway. Screening of patients with primary lymphedema identified\n                    <jats:italic>PLXND1<\/jats:italic>\n                    missense variants, and functional analysis established 2 pathogenic variants that selectively disrupt the ligand versus mechanosensing functions of this receptor. Variants associated with lymphedema in members of the mechanocomplex disrupted its formation, underscoring the central role of this complex in lymphatic valve biology. Our work uncovers a mechanosensing mechanism guiding lymphatic valve development, and has profound implications for the understanding and treatment of primary lymphedema in humans.\n                  <\/jats:p>","DOI":"10.1172\/jci193385","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:30:13Z","timestamp":1782844213000},"source":"Crossref","is-referenced-by-count":3,"title":["Mechanoreceptor plexin D1 regulates lymphatic valve morphogenesis and lymphedema pathogenesis"],"prefix":"10.1172","volume":"136","author":[{"given":"Kar-Lai","family":"Pang","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Radcliffe Department of Medicine, and"},{"name":"Centre for Human Genetics, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vedanta","family":"Mehta","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Radcliffe Department of Medicine, and"},{"name":"Centre for Human Genetics, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Aitken","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Radcliffe Department of Medicine, and"},{"name":"Centre for Human Genetics, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Dobbins","sequence":"additional","affiliation":[{"name":"School of Health and Medical Sciences, City St George\u2019s University of London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yu","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, University of Oxford, Oxford, United Kingdom."},{"name":"Division of Structural Biology, Centre for Human Genetics, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Bonetti","sequence":"additional","affiliation":[{"name":"MAGI Euregio, Bolzano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam N.","family":"Keen","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Radcliffe Department of Medicine, and"},{"name":"Centre for Human Genetics, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Radcliffe Department of Medicine, and"},{"name":"Centre for Human Genetics, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00e9lie","family":"Sabine","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research, Lausanne, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana V.","family":"Petrova","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research, Lausanne, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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