{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T01:47:13Z","timestamp":1789264033794,"version":"build-2803163510"},"reference-count":66,"publisher":"SAGE Publications","issue":"15","license":[{"start":{"date-parts":[[2020,7,30]],"date-time":"2020-07-30T00:00:00Z","timestamp":1596067200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Stem Cells and Development"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:p>\n                    Congenital diaphragmatic hernia (CDH) leads to pathophysiologic pulmonary vasoreactivity. Previous studies show that mesenchymal stromal cell-derived extracellular vesicles (MSCEv) inhibit lung inflammation and vascular remodeling. We characterize MSCEv and human pulmonary artery endothelial cell (HPAEC) interaction, as well as the pulmonary artery (PA) response to MSCEv treatment. HPAECs were cultured with and without exposure to nitrofen (2,4-dichloro-phenyl-p-nitrophenylether) and treated with MSCEv. HPAEC viability, architecture, production of reactive oxygen species (ROS), endothelial dysfunction-associated protein levels (PPAR\u03b3, LOX-1, LOX-2, nuclear factor-\u03baB [NF-\u03baB], endothelial NO synthase [eNOS], ET-1 [endothelin 1]), and the nature of MSCEv-cellular interaction were assessed. Newborn rodents with and without CDH (nitrofen model and Sprague-Dawley) were treated with intravascular MSCEv or vehicle control, and their PAs were isolated. Contractility was assessed by wire myography. The contractile (KCL and ET-1) and relaxation (fasudil) responses were evaluated. HPAEC viability correlated inversely with nitrofen dose, while architectural compromise was directly proportional. There was a 2.1\u2009\u00d7\u2009increase in ROS levels in nitrofen HPAECs (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009&lt;\u20090.001), and MSCEv treatment attenuated ROS levels by 1.5\u2009\u00d7\u2009versus nitrofen HPAECs (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009&lt;\u20090.01). Nitrofen-induced alterations in endothelial dysfunction-associated proteins are shown, and exposure to MSCEv restored more physiologic expression. Nitrofen HPAEC displayed greater MSCEv uptake (80% increase,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009&lt;\u20090.05). Adenosine, a clathrin-mediated endocytosis inhibitor, decreased uptake by 46% (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009&lt;\u20090.05). CDH PA contraction was impaired with KCL (108.6%\u2009\u00b1\u20091.4% vs. 112.0%\u2009\u00b1\u20091.4%,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009=\u20090.092) and ET-1 (121.7%\u2009\u00b1\u20093.0% vs. 131.2%\u2009\u00b1\u20091.8%,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009&lt;\u20090.01). CDH PA relaxation was impaired with fasudil (32.2%\u2009\u00b1\u20091.9% vs. 42.1%\u2009\u00b1\u20092.2%,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009&lt;\u20090.001). After MSCEv treatment, CDH PA contraction improved (125.9%\u2009\u00b1\u20093.4% vs. 116.4\u2009\u00b1\u20093.5,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009=\u20090.06), and relaxation was unchanged (32.5%\u2009\u00b1\u20093.2% vs. 29.4%\u2009\u00b1\u20093.1%,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u2009=\u20090.496). HPAEC exposure to nitrofen led to changes consistent with vasculopathy in CDH, and MSCEv treatment led to a more physiologic cellular response. MSCEv were preferentially taken up by nitrofen-treated cells by clathrin-dependent endocytosis. In vivo, MSCEv exposure improved PA contractile response. These data reveal mechanisms of cellular and signaling alterations that characterize MSCEv-mediated attenuation of pulmonary vascular dysfunction in CDH-associated pulmonary hypertension.\n                  <\/jats:p>","DOI":"10.1089\/scd.2020.0063","type":"journal-article","created":{"date-parts":[[2020,5,30]],"date-time":"2020-05-30T07:58:17Z","timestamp":1590825497000},"page":"967-980","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":16,"title":["Extracellular Vesicles Attenuate Nitrofen-Mediated Human Pulmonary Artery Endothelial Dysfunction: Implications for Congenital Diaphragmatic Hernia"],"prefix":"10.1177","volume":"29","author":[{"given":"Siqin","family":"Zhaorigetu","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School at the University of Texas Health Science Center (UTHealth) and Children's Memorial Hermann Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Bair","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School at the University of Texas Health Science Center (UTHealth) and Children's Memorial Hermann Hospital, Houston, Texas, USA."},{"name":"Stanford University School of Medicine, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School at the University of Texas Health Science Center (UTHealth) and Children's Memorial Hermann Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas S.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School at the University of Texas Health Science Center (UTHealth) and Children's Memorial Hermann Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavannya M.","family":"Pandit","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Bryan","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P.","family":"Lally","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School at the University of Texas Health Science Center (UTHealth) and Children's Memorial Hermann Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School at the University of Texas Health Science Center (UTHealth) and Children's Memorial Hermann Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles S.","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School at the University of Texas Health Science Center (UTHealth) and Children's Memorial Hermann Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew T.","family":"Harting","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School at the University of Texas Health Science Center (UTHealth) and Children's Memorial Hermann Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,7,30]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12098-010-0094-1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0161334"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1159\/000484087"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3468(90)90190-K"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.3171\/2008.9.JNS08158"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2015-0065"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2730"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.114173"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2009.12.003"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.20-6-530"},{"key":"e_1_3_4_12_2","first-page":"315","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells","volume":"8","author":"Dominici M","year":"2006","unstructured":"Dominici M, , Le Blanc K, , Mueller I, , Slaper-Cortenbach I, , Marini F, , Krause D, , Deans R, , Keating A, , Prockop D, and Horwitz E. 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