{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T15:48:10Z","timestamp":1777564090486,"version":"3.51.4"},"reference-count":73,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,5,8]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>\n              The PTH1R (PTH [parathyroid hormone]\/PTHrP [PTH-related protein] receptor) is expressed in vascular smooth muscle (VSM) and increased VSM PTH1R signaling mitigates diet-induced arteriosclerosis in LDLR\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>\n              To study the impact of VSM PTH1R deficiency, we generated mice SM22-Cre:PTH1R(fl\/fl);LDLR\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice (PTH1R-VKO) and Cre-negative controls.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              Immunofluorescence and Western blot confirmed PTH1R expression in arterial VSM that was reduced by Cre-mediated knockout. PTH1R-VKO cohorts exhibited increased aortic collagen accumulation in vivo, and VSM cultures from PTH1R-VKO mice elaborated more collagen (2.5-fold;\n              <jats:italic>P<\/jats:italic>\n              =0.01) with elevated\n              <jats:italic>Col3a1<\/jats:italic>\n              and\n              <jats:italic>Col1a1<\/jats:italic>\n              expression. To better understand these profibrotic responses, we performed mass spectrometry on nuclear proteins extracted from Cre-negative controls and PTH1R-VKO VSM. PTH1R deficiency reduced Gata6 but upregulated the MADS (MCM1, Agamous, Deficiens, and Srf DNA-binding domain)-box transcriptional co-regulator, Mkl-1 (megakaryoblastic leukemia [translocation] 1). Co-transfection assays (\n              <jats:italic>Col3a1<\/jats:italic>\n              promoter-luciferase reporter) confirmed PTH1R-mediated inhibition and Mkl-1-mediated activation of\n              <jats:italic>Col3a1<\/jats:italic>\n              transcription. Regulation mapped to a conserved hybrid CT(A\/T)\n              <jats:sub>6<\/jats:sub>\n              GG MADS-box cognate in the\n              <jats:italic>Col3a1<\/jats:italic>\n              promoter. Mutations of C\/G in this motif markedly reduced\n              <jats:italic>Col3a1<\/jats:italic>\n              transcriptional regulation by PTH1R and Mkl-1. Upregulation of\n              <jats:italic>Col3a1<\/jats:italic>\n              and\n              <jats:italic>Col1a1<\/jats:italic>\n              in PTH1R-VKO VSM was inhibited by small interfering RNA targeting\n              <jats:italic>Mkl1<\/jats:italic>\n              and by treatment with the Mkl-1 antagonist CCG1423 or the Rock (Rho-associated coiled-coil containing protein kinase)-2 inhibitor KD025. Chromatin precipitation demonstrated that VSM PTH1R deficiency increased Mkl-1 binding to\n              <jats:italic>Col3a1 and Col1a1<\/jats:italic>\n              , but not\n              <jats:italic>TNF<\/jats:italic>\n              , promoters. Proteomic studies of plasma extracellular vesicles and VSM from PTH1R-VKO mice identified C1r (complement component 1, r) and C1s (complement component 1, s), complement proteins involved in vascular collagen metabolism, as potential biomarkers. VSM C1r protein and\n              <jats:italic>C1r<\/jats:italic>\n              message were increased with PTH1R deficiency, mediated by Mkl-1-dependent transcription and inhibited by CCG1423 or KD025.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>PTH1R signaling restricts collagen production in the VSM lineage, in part, via Mkl-1 regulatory circuits that control collagen gene transcription. Strategies that maintain homeostatic VSM PTH1R signaling, as reflected in extracellular vesicle biomarkers of VSM PTH1R\/Mkl-1 action, may help mitigate arteriosclerosis and vascular fibrosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.119.316141","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T18:32:23Z","timestamp":1584556343000},"page":"1363-1378","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["PTH\/PTHrP Receptor Signaling Restricts Arterial Fibrosis in Diabetic LDLR\n            <sup>\u2212\/\u2212<\/sup>\n            Mice by Inhibiting Myocardin-Related Transcription Factor Relays"],"prefix":"10.1161","volume":"126","author":[{"given":"Abraham","family":"Behrmann","sequence":"first","affiliation":[{"name":"From the Internal Medicine, Endocrine Division (A.B., D.Z., L.L., S.-L.C., M.M., B.R., P.S., D.A.T.), UT Southwestern Medical Center, Dallas, 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