{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:17Z","timestamp":1790189957759,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>The phenotypic switching of vascular smooth muscle cells (VSMCs) is a critical pathophysiological mechanism of diabetic vascular remodeling. There is increasing evidence indicating that endogenous relaxin-3 exhibits cardiovascular effects, including vasodilation, reversal of ventricular remodeling, and attenuation of myocardial fibrosis. This study investigates the role of relaxin-3 as a key regulator in the phenotypic switching of VSMCs and elucidates its underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We generated a diabetic rat model to investigate the biological roles of relaxin-3 in diabetic vascular remodeling. Metabolomic profiling characterized relaxin-3-induced metabolic changes in VSMCs under high glucose treatment. Combined chromatin immunoprecipitation sequencing and RNA sequencing data were used to further investigate the gene regulatory mechanisms of relaxin-3 in the phenotypic switching of VSMCs and target genes regulated by H3K18la (histone H3 lysine 18 lactylation).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Relaxin-3 and its receptor RXFP1 (relaxin family peptide receptor 1) were upregulated in diabetic human and rat aortas. Silencing of relaxin-3 or RXFP1 expression inhibited VSMC contractile phenotype protein expression and promoted VSMC proliferation. Relaxin-3 treatment mitigated the phenotypic switching of VSMCs via RXFP1, preserving VSMCs\u2019 contractile phenotype. Further, relaxin-3 treatment lowered the glycolytic rate and lactate production during the phenotypic switching of VSMCs and decreased histone lactylation. Mechanistically, relaxin-3 suppressed LDHA (lactate dehydrogenase A)-mediated lactate production and H3K18la-mediated\n                      <jats:italic toggle=\"yes\">Egfr<\/jats:italic>\n                      (epidermal growth factor receptor) transcription, and blocked PKM2 (pyruvate kinase M2) nuclear translocation, thereby preventing PKM2\/\u03b2-catenin complex formation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Relaxin-3 alleviated the phenotypic switching of diabetic VSMCs through a dual mechanism: inhibiting lactate-mediated H3K18la and disrupting the intranuclear PKM2\/\u03b2-catenin interaction, thereby preserving the contractile VSMC phenotype.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324338","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:00:21Z","timestamp":1787821221000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Relaxin-3\/RXFP1 Axis Regulates the Phenotypic Switch of Diabetic Vascular Smooth Muscle Cells by Inhibiting H3K18la-Mediated Egfr Transcription"],"prefix":"10.1161","volume":"46","author":[{"given":"Jiaxin","family":"Xue","sequence":"first","affiliation":[{"name":"The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, China (J.X., J.W., Y.Y., X. Liang, X. Liu, S.H., X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0924-9538","authenticated-orcid":true,"given":"Jingzhi","family":"Wang","sequence":"additional","affiliation":[{"name":"The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, China (J.X., J.W., Y.Y., X. Liang, X. Liu, S.H., X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3005-5539","authenticated-orcid":true,"given":"Yuxin","family":"Yang","sequence":"additional","affiliation":[{"name":"The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, China (J.X., J.W., Y.Y., X. Liang, X. Liu, S.H., X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3299-0173","authenticated-orcid":true,"given":"Xinfang","family":"Liang","sequence":"additional","affiliation":[{"name":"The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, China (J.X., J.W., Y.Y., X. Liang, X. Liu, S.H., X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9228-8688","authenticated-orcid":true,"given":"Xiaoqi","family":"Liu","sequence":"additional","affiliation":[{"name":"The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, China (J.X., J.W., Y.Y., X. Liang, X. Liu, S.H., X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8637-8714","authenticated-orcid":true,"given":"Siting","family":"Hong","sequence":"additional","affiliation":[{"name":"The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, China (J.X., J.W., Y.Y., X. Liang, X. 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