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However, the etiology of pulmonary vascular endothelial cell (EC) dysfunction, an established precursor to PVD, is incompletely understood but may involve abnormal blood flow patterns, hypoxemia, and polycythemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Hypothesis<\/jats:title>\n                    <jats:p>Utilizing an ovine Glenn model, we hypothesized that nonpulsatile pulmonary blood flow (PBF) induces pulmonary vascular EC dysfunction, independent of hypoxemia or polycythemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Seven lambs (6\u20138\u2009weeks old) underwent a Glenn procedure. Eight weeks later, Glenn and age\u2010matched controls were studied. The response to the endothelium\u2010dependent vasodilator acetylcholine (Ach) was determined in isolated pulmonary arteries (PA). Nitric oxide (NO) and endothelin\u20101 (ET\u20101) signaling were determined in right lung tissues. Indices of cell proliferation, angiogenesis, and apoptosis were determined in PA endothelial cells (PAECs). Comparisons were made by unpaired\n                      <jats:italic>t<\/jats:italic>\n                      \u2010test and ANOVA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      There were no differences in age, hemoglobin, or oxygen saturation between groups. Mean PA pressure and left PA flow were higher, and right lung blood flow was lower in Glenn lambs compared to controls (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). All other baseline hemodynamics were similar. Glenn PAs had impaired relaxation to Ach. Glenn lung NO metabolite levels (NOx) and eNOS protein were lower, and ET\u20101 levels and prepro\u2010ET\u20101 protein were higher than controls (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Glenn PAECs had higher rates of proliferation and angiogenesis, and decreased apoptosis (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The initiation of nonpulsatile PBF following the Glenn induces early EC dysfunction independent of hypoxemia and polycythemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cph4.70071","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T04:01:21Z","timestamp":1762833681000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pulmonary Vascular Endothelial Dysfunction Is Induced by Nonpulsatile Pulmonary Blood Flow in an Ovine Classic Glenn Model"],"prefix":"10.1002","volume":"15","author":[{"given":"Jonathan","family":"Hyde","sequence":"first","affiliation":[{"name":"Division of Pediatric Critical Care, Department of Pediatrics University of California  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7899-7248","authenticated-orcid":false,"given":"Michael A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Pediatric Critical Care, Department of Pediatrics University of California  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naveen","family":"Swami","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiothoracic Surgery, Department of Surgery University of California  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John H.","family":"Hwang","sequence":"additional","affiliation":[{"name":"Division of Pediatric Critical Care, Department of Pediatrics University of California  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yenchun","family":"Chao","sequence":"additional","affiliation":[{"name":"Division of Pediatric Critical Care, Department of Pediatrics University of California  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4908-9934","authenticated-orcid":false,"given":"Jason","family":"Boehme","sequence":"additional","affiliation":[{"name":"Division of Pediatric Critical Care, Department of Pediatrics University of California  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary W.","family":"Raff","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiothoracic Surgery, Department of Surgery University of California  Davis California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casper Noah","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Division of Pediatric Critical Care, Department of Pediatrics University of California  San Francisco California USA"},{"name":"Department of Cardiothoracic Surgery Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhui","family":"Gong","sequence":"additional","affiliation":[{"name":"Division of Pediatric Critical Care, Department of Pediatrics University of California  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail H.","family":"Deutsch","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle Washington 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