{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:45:56Z","timestamp":1790361956021,"version":"4.1.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,5,24]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              <jats:italic toggle=\"yes\">Gli1<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">Cre-ERT2<\/jats:italic>\n              <\/jats:sup>\n              <jats:italic toggle=\"yes\">; tdTomato<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">flox<\/jats:italic>\n              <\/jats:sup>\n              mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an\n              <jats:italic toggle=\"yes\">Acta2<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">high<\/jats:italic>\n              <\/jats:sup>\n              fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.123.323736","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T09:00:50Z","timestamp":1713517250000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["GLI1+ Cells Contribute to Vascular Remodeling in Pulmonary Hypertension"],"prefix":"10.1161","volume":"134","author":[{"given":"Xuran","family":"Chu","sequence":"first","affiliation":[{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) (X.C., S.B.), Wenzhou Medical University, China."},{"name":"School of Pharmaceutical Sciences (X.C., X.L.), Wenzhou Medical University, China."},{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vahid","family":"Kheirollahi","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun","family":"Lingampally","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Chelladurai","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanil","family":"Valasarajan","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Ivonne","family":"Vazquez-Armendariz","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. 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Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg","family":"Pak","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4550-4945","authenticated-orcid":true,"given":"Stefano","family":"Rivetti","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5544-9647","authenticated-orcid":true,"given":"Jochen","family":"Wilhelm","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6872-9082","authenticated-orcid":true,"given":"Marek","family":"Bartkuhn","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0820-3318","authenticated-orcid":true,"given":"Slaven","family":"Crnkovic","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research, Medical University Graz, Austria (S.C., G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-2873","authenticated-orcid":true,"given":"Alena","family":"Moiseenko","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Heiner","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5856-8211","authenticated-orcid":true,"given":"Simone","family":"Kraut","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila Sotoodeh","family":"Atefi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Koepke","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme","family":"Valente","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Lung and Heart, Bad Nauheim, Germany (G.V., T.B., M.L., W.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-2469","authenticated-orcid":true,"given":"Clemens","family":"Ruppert","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-4804","authenticated-orcid":true,"given":"Thomas","family":"Braun","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Lung and Heart, Bad Nauheim, Germany (G.V., T.B., M.L., W.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9153-6040","authenticated-orcid":true,"given":"Christos","family":"Samakovlis","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5601-2831","authenticated-orcid":true,"given":"Ioannis","family":"Alexopoulos","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. 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Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany."},{"name":"Department of Pediatrics, HELIOS University Medical Center, Witten\/Herdecke University, Wuppertal, Germany (C.-M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6343-0911","authenticated-orcid":true,"given":"Susanne","family":"Herold","sequence":"additional","affiliation":[{"name":"Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. 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