{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:55:46Z","timestamp":1790916946284,"version":"4.1.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pulmonary hypertension (PH) is characterized by progressive pulmonary vascular remodeling driven by activation of pulmonary arterial smooth muscle cells (PASMCs). Resolvin D1 (RvD1), a specialized pro-resolving lipid mediator derived from docosahexaenoic acid (DHA), has vascular protective actions; however, its pharmacological effect on connexin 43 (Cx43)-mediated gap junctional intercellular communication in PH remains unclear. This study investigated whether RvD1 attenuates PH by suppressing pathological formation of gap-junctional Cx43 (GJs-Cx43) in PASMCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      SU5416\/hypoxia-induced PH was established in C57BL\/6 mice.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , primary mouse PASMCs were cultured under hypoxic conditions to mimic the hypoxic pathological microenvironment and PASMCs activation associated with PH. Pulmonary hemodynamics, right ventricular function and hypertrophy, pulmonary arterial remodeling, and Cx43 distribution in isolated small pulmonary arteries were evaluated\n                      <jats:italic>in vivo<\/jats:italic>\n                      . In PASMCs, biochemical fractionation, Western blotting, immunofluorescence, lucifer yellow dye transfer, cell proliferation and migration assays, and inflammatory and oxidative stress assessments were performed. ZP1609 was used to enhance GJs-Cx43 function\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RvD1 improved pulmonary hemodynamics and right ventricular adaptation in SU5416\/hypoxia-exposed mice. RvD1 also reduced pulmonary arterial wall thickening, elastic lamina remodeling, \u03b1-SMA accumulation and PCNA-positive proliferating cells. Mechanistically, SU5416\/hypoxia increased total Cx43 and shifted Cx43 toward the GJs-Cx43 formation. RvD1 inhibited GJs-Cx43 formation and attenuated IL-1\u03b2, IL-6, ROS and MDA accumulation while partially restoring SOD. In primary PASMCs, hypoxia increased GJs-Cx43 expression, enhanced lucifer yellow dye transfer, and promoted proliferation and migration; these changes were suppressed by RvD1. ZP1609 restored GJs-Cx43-mediated intercellular communication and weakened the inhibitory effects of RvD1 on PASMC inflammatory activation, oxidative stress, proliferation and migration.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , ZP1609 similarly blunted the protection conferred by RvD1 against pulmonary vascular remodeling, right ventricular pressure overload and right ventricular hypertrophy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Pathological GJs-Cx43 formation promotes the spread of remodeling-associated signals across PASMCs networks. RvD1 limits pulmonary vascular remodeling by suppressing Cx43-dependent gap junctional communication, identifying GJs-Cx43 as a pharmacologically relevant mechanism underlying the vascular protection afforded by this DHA-derived lipid mediator.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1940174","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:37:17Z","timestamp":1790915837000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Resolvin D1 attenuates pulmonary hypertension by suppressing pathological connexin 43-mediated gap junctional communication in pulmonary arterial smooth muscle cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Hong","family":"Wang","sequence":"first","affiliation":[{"name":"Heart Center, Qingdao Women and Children\u2019s Hospital, Shandong University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"Endoscopy Center, Qingdao Municipal Hospital (Qingdao Hospital, University of Health and Rehabilitation Sciences)","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixian","family":"Ji","sequence":"additional","affiliation":[{"name":"Heart Center, Qingdao Women and Children\u2019s Hospital, Shandong University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Heart Center, Qingdao Women and Children\u2019s Hospital, Shandong University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Qingdao Municipal Hospital (Qingdao Hospital, University of Health and Rehabilitation Sciences)","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silin","family":"Pan","sequence":"additional","affiliation":[{"name":"Heart Center, Qingdao Women and Children\u2019s Hospital, Shandong University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s12989-022-00495-6","article-title":"Enhanced silver nanoparticle-induced pulmonary inflammation in a metabolic syndrome mouse model and resolvin D1 treatment","volume":"19","author":"Alqahtani","year":"2022","journal-title":"Part Fibre Toxicol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"106151","DOI":"10.1016\/j.phrs.2022.106151","article-title":"1,8-Cineole ameliorates right ventricle dysfunction associated with pulmonary arterial hypertension by restoring connexin43 and mitochondrial homeostasis","volume":"180","author":"Alves-Silva","year":"2022","journal-title":"Pharmacol. 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