{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T23:55:17Z","timestamp":1786578917376,"version":"build-2736575974"},"reference-count":34,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T00:00:00Z","timestamp":1714953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T00:00:00Z","timestamp":1714953600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL156866"],"award-info":[{"award-number":["HL156866"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Angiopoietin\u20102 (Ang\u20102) is increased in the blood of patients with kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE). While the genetic causes of KHE are not clear, a somatic activating NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      mutation has been found in the lesions of KLA patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Procedure<\/jats:title>\n                    <jats:p>\n                      Our study tested the hypothesis that the NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      mutation drives elevated Ang\u20102 expression in endothelial cells. Ang\u20102 was measured in human endothelial progenitor cells (EPC) expressing NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      and a genetic mouse model with endothelial targeted NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      . To determine the signaling pathways driving Ang\u20102, NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      EPC were treated with signaling pathway inhibitors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ang\u20102 levels were increased in EPC expressing NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      compared to NRAS\n                      <jats:sup>WT<\/jats:sup>\n                      by Western blot analysis of cell lysates and ELISA of the cell culture media. Ang\u20102 levels were elevated in the blood of NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      mutant mice. NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      mutant mice also had reduced platelet counts and splenomegaly with hypervascular lesions, like some KLA patients. mTOR inhibitor rapamycin attenuated Ang\u20102 expression by NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      EPC. However, MEK1\/2 inhibitor trametinib was more effective blocking increases in Ang\u20102.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our studies show that the NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      mutation in endothelial cells induces Ang\u20102 expression in vitro and in vivo. In cultured human endothelial cells, NRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                      drives elevated Ang\u20102 through MAP kinase and mTOR\u2010dependent signaling pathways.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pbc.31032","type":"journal-article","created":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T23:38:29Z","timestamp":1715038709000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["NRAS\n                    <sup>Q61R<\/sup>\n                    mutation drives elevated angiopoietin\u20102 expression in human endothelial cells and a genetic mouse model"],"prefix":"10.1002","volume":"71","author":[{"given":"Patricia","family":"Pastura","sequence":"first","affiliation":[{"name":"Division of Pulmonary Biology, Department of Pediatrics Cincinnati Children's Hospital Medical Center &amp; University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Griffin","family":"McDaniel","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Department of Pediatrics Cincinnati Children's Hospital Medical Center &amp; University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Department of Pediatrics Cincinnati Children's Hospital Medical Center &amp; University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dermot","family":"Fox","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Department of Pediatrics Cincinnati Children's Hospital Medical Center &amp; University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Molecular &amp; Cellular Biosciences University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5770-7280","authenticated-orcid":false,"given":"Punam","family":"Malik","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Department of Pediatrics Cincinnati Children's Hospital Medical Center &amp; University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise M.","family":"Adams","sequence":"additional","affiliation":[{"name":"Division of Oncology Comprehensive Vascular Anomalies Program Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-2703","authenticated-orcid":false,"given":"Timothy D.","family":"Le Cras","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Department of Pediatrics Cincinnati Children's Hospital Medical Center &amp; 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