{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:49:47Z","timestamp":1790596187221,"version":"4.1.0"},"reference-count":132,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2018,9,28]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Mutations in\n                      <jats:italic>GJC2<\/jats:italic>\n                      and\n                      <jats:italic>GJA1<\/jats:italic>\n                      , encoding Cxs (connexins) 47 and 43, respectively, are linked to lymphedema, but the underlying mechanisms are unknown. Because efficient lymph transport relies on the coordinated contractions of lymphatic muscle cells (LMCs) and their electrical coupling through Cxs, Cx-related lymphedema is proposed to result from dyssynchronous contractions of lymphatic vessels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>To determine which Cx isoforms in LMCs and lymphatic endothelial cells are required for the entrainment of lymphatic contraction waves and efficient lymph transport.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>We developed novel methods to quantify the spatiotemporal entrainment of lymphatic contraction waves and used optogenetic techniques to analyze calcium signaling within and between the LMC and the lymphatic endothelial cell layers. Genetic deletion of the major lymphatic endothelial cell Cxs (Cx43, Cx47, or Cx37) revealed that none were necessary for the synchronization of the global calcium events that triggered propagating contraction waves. We identified Cx45 in human and mouse LMCs as the critical Cx mediating the conduction of pacemaking signals and entrained contractions. Smooth muscle\u2013specific Cx45 deficiency resulted in 10- to 18-fold reduction in conduction speed, partial-to-severe loss of contractile coordination, and impaired lymph pump function ex vivo and in vivo. Cx45 deficiency resulted in profound inhibition of lymph transport in vivo, but only under an imposed gravitational load.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Our results (1) identify Cx45 as the Cx isoform mediating the entrainment of the contraction waves in LMCs; (2) show that major endothelial Cxs are dispensable for the entrainment of contractions; (3) reveal a lack of coupling between lymphatic endothelial cells and LMCs, in contrast to arterioles; (4) point to lymphatic valve defects, rather than contraction dyssynchrony, as the mechanism underlying\n                      <jats:italic>GJC2<\/jats:italic>\n                      - or\n                      <jats:italic>GJA1<\/jats:italic>\n                      -related lymphedema; and (5) show that a gravitational load exacerbates lymphatic contractile defects in the intact mouse hindlimb, which is likely critical for the development of lymphedema in the adult mouse.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.117.312576","type":"journal-article","created":{"date-parts":[[2018,9,29]],"date-time":"2018-09-29T01:27:28Z","timestamp":1538184448000},"page":"964-985","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":84,"title":["Mechanisms of Connexin-Related Lymphedema"],"prefix":"10.1161","volume":"123","author":[{"given":"Jorge A.","family":"Castorena-Gonzalez","sequence":"first","affiliation":[{"name":"From the Department of Medical Pharmacology and Physiology (J.A.C.-G., S.D.Z., M.L., L.A.M.-L., M.J.D.), University of Missouri, Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Zawieja","sequence":"additional","affiliation":[{"name":"From the Department of Medical Pharmacology and Physiology (J.A.C.-G., S.D.Z., M.L., L.A.M.-L., M.J.D.), University of Missouri, Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"From the Department of Medical Pharmacology and Physiology (J.A.C.-G., S.D.Z., M.L., L.A.M.-L., M.J.D.), University of Missouri, Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Sathish","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (R.S.S.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M.","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Arizona, Tucson (A.M.S.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cor","family":"de Wit","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Luebeck, Germany (C.d.W.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"de la Torre","sequence":"additional","affiliation":[{"name":"Department of Medicine (R.d.l.T.), University of Missouri, Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis A.","family":"Martinez-Lemus","sequence":"additional","affiliation":[{"name":"From the Department of Medical Pharmacology and Physiology (J.A.C.-G., S.D.Z., M.L., L.A.M.-L., M.J.D.), University of Missouri, Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant W.","family":"Hennig","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Vermont, Burlington (G.W.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Davis","sequence":"additional","affiliation":[{"name":"From the Department of Medical Pharmacology and Physiology (J.A.C.-G., S.D.Z., M.L., L.A.M.-L., M.J.D.), University of Missouri, Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.04.010"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2010.085563"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2303"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12158"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.10.022"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.04.004"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.12.020"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.130401"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2002.tb04867.x"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1980.239.6.H775"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-008-0259-z"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.7861\/clinmedicine.4-5-448"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1413.014"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1076-6332(05)80193-X"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.39.6.723"},{"key":"e_1_3_5_17_2","first-page":"13","article-title":"Impact of manual lymphatic drainage on hemodynamic parameters in patients with heart failure and lower limb edema.","volume":"44","author":"Leduc O","year":"2011","unstructured":"Leduc, O, Crasset, V, Leleu, C, Baptiste, N, Koziel, A, Delahaie, C, Pastouret, F, Wilputte, F, Leduc, A. 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