{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T09:22:39Z","timestamp":1791969759944,"version":"4.3.4"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T00:00:00Z","timestamp":1658016000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims:<\/jats:title>\n                    <jats:p>\n                      In hereditary hemorrhagic telangiectasia (HHT), severe liver vascular malformations are associated with mutations in the Activin A Receptor\u2010Like Type 1 (\n                      <jats:italic toggle=\"yes\">ACVRL1<\/jats:italic>\n                      ) gene encoding ALK1, the receptor for bone morphogenetic protein (BMP) 9\/BMP10, which regulates blood vessel development. Here, we established an HHT mouse model with exclusive liver involvement and adequate life expectancy to investigate ALK1 signaling in liver vessel formation and metabolic function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results:<\/jats:title>\n                    <jats:p>\n                      Liver sinusoidal endothelial cell (LSEC)\u2010selective Cre deleter line,\n                      <jats:italic toggle=\"yes\">Stab2\u2010iCreF3<\/jats:italic>\n                      , was crossed with\n                      <jats:italic toggle=\"yes\">Acvrl1<\/jats:italic>\n                      \u2010floxed mice to generate LSEC\u2010specific\n                      <jats:italic toggle=\"yes\">Acvrl1<\/jats:italic>\n                      \u2010deficient mice (\n                      <jats:italic toggle=\"yes\">Alk1<\/jats:italic>\n                      <jats:sup>HEC\u2010KO<\/jats:sup>\n                      ).\n                      <jats:italic toggle=\"yes\">Alk1<\/jats:italic>\n                      <jats:sup>HEC\u2010KO<\/jats:sup>\n                      mice revealed hepatic vascular malformations and increased posthepatic flow, causing right ventricular volume overload. Transcriptomic analyses demonstrated induction of proangiogenic\/tip cell gene sets and arterialization of hepatic vessels at the expense of LSEC and central venous identities. Loss of LSEC angiokines\n                      <jats:italic toggle=\"yes\">Wnt2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Wnt9b<\/jats:italic>\n                      , and R\u2010spondin\u20103 (\n                      <jats:italic toggle=\"yes\">Rspo3<\/jats:italic>\n                      ) led to disruption of metabolic liver zonation in\n                      <jats:italic toggle=\"yes\">Alk1<\/jats:italic>\n                      <jats:sup>HEC\u2010KO<\/jats:sup>\n                      mice and in liver specimens of patients with HHT. Furthermore, prion\u2010like protein doppel (\n                      <jats:italic toggle=\"yes\">Prnd<\/jats:italic>\n                      ) and placental growth factor (\n                      <jats:italic toggle=\"yes\">Pgf<\/jats:italic>\n                      ) were upregulated in\n                      <jats:italic toggle=\"yes\">Alk1<\/jats:italic>\n                      <jats:sup>HEC\u2010KO<\/jats:sup>\n                      hepatic endothelial cells, representing candidates driving the organ\u2010specific pathogenesis of HHT. In LSEC\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , stimulation or inhibition of ALK1 signaling counter\u2010regulated Inhibitors of DNA binding (ID)1\u20133, known Alk1 transcriptional targets. Stimulation of ALK1 signaling and inhibition of ID1\u20133 function confirmed regulation of\n                      <jats:italic toggle=\"yes\">Wnt2<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Rspo3<\/jats:italic>\n                      by the BMP9\/ALK1\/ID axis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Hepatic endothelial ALK1 signaling protects from development of vascular malformations preserving organ\u2010specific endothelial differentiation and angiocrine signaling. The long\u2010term surviving\n                      <jats:italic toggle=\"yes\">Alk1<\/jats:italic>\n                      <jats:sup>HEC\u2010KO<\/jats:sup>\n                      HHT model offers opportunities to develop targeted therapies for this severe disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32641","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T12:45:38Z","timestamp":1656679538000},"page":"1211-1227","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":36,"title":["ALK1 controls hepatic vessel formation, angiodiversity, and angiocrine functions in hereditary hemorrhagic telangiectasia of the liver"],"prefix":"10.1097","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4401-3394","authenticated-orcid":false,"given":"Christian David","family":"Schmid","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6083-5534","authenticated-orcid":false,"given":"Victor","family":"Olsavszky","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Reinhart","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Weyer","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"Department of Radiation Oncology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix A.","family":"Trogisch","sequence":"additional","affiliation":[{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), partner site Heidelberg\/Mannheim, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Sticht","sequence":"additional","affiliation":[{"name":"Core Facility Platform Mannheim, NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2415-9350","authenticated-orcid":false,"given":"Manuel","family":"Winkler","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina W.","family":"K\u00fcrschner","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2774-7847","authenticated-orcid":false,"given":"Johannes","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana","family":"Ola","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Staniczek","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Heineke","sequence":"additional","affiliation":[{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), partner site Heidelberg\/Mannheim, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate K.","family":"Straub","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center of the Johannes Gutenberg\u2010University Mainz, Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Mittler","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, and Transplant Surgery, University Medical Center of the Johannes Gutenberg\u2010University Mainz, Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Schledzewski","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"ten Dijke","sequence":"additional","affiliation":[{"name":"Oncode Institute, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Richter","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Dooley","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrill","family":"G\u00e9raud","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"Section of Clinical 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