{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:46:54Z","timestamp":1792007214043,"version":"4.4.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Computational modeling indicated that pathological high shear stress (HSS; 100 dyn\/cm\n                      <jats:sup>2<\/jats:sup>\n                      ) is generated in pulmonary arteries (PAs; 100\u2013500 \u00b5m) in congenital heart defects causing PA hypertension (PAH) and in idiopathic PAH with occlusive vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) is a feature of PAH. We hypothesize that HSS induces EndMT, contributing to the initiation and progression of PAH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We used the Ibidi perfusion system to determine whether HSS applied to human PA endothelial cells (ECs) induces EndMT when compared with physiological laminar shear stress (15 dyn\/cm\n                      <jats:sup>2<\/jats:sup>\n                      ). The mechanism was investigated and targeted to prevent PAH in a mouse with HSS induced by an aortocaval shunt.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>EndMT, a feature of PAH not previously attributed to HSS, was observed. HSS did not alter the induction of transcription factors KLF (Kr\u00fcppel-like factor) 2\/4, but an ERG (ETS-family transcription factor) was reduced, as were histone H3 lysine 27 acetylation enhancer-promoter peaks containing ERG motifs. Consequently, there was reduced interaction between ERG and KLF2\/4, a feature important in tethering KLF and the chromatin remodeling complex to DNA. In PA ECs under laminar shear stress, reducing ERG by siRNA caused EndMT associated with decreased BMPR2 (bone morphogenetic protein receptor 2), CDH5 (cadherin 5), and PECAM1 (platelet and EC adhesion molecule 1) and increased SNAI1\/2 (Snail\/Slug) and ACTA2 (smooth muscle \u03b12 actin). In PA ECs under HSS, transfection of ERG prevented EndMT. HSS was then induced in mice by an aortocaval shunt, causing progressive PAH over 8 weeks. An adeno-associated viral vector (AAV2-ESGHGYF) was used to replenish ERG selectively in PA ECs. Elevated PA pressure, EndMT, and vascular remodeling (muscularization of peripheral arteries) in the aortocaval shunt mice were markedly reduced by ERG delivery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Pathological HSS reduced lung EC ERG, resulting in EndMT and PAH. Agents that upregulate ERG could reverse HSS-mediated PAH and occlusive vascular remodeling resulting from high flow or narrowed PAs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.124.321092","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T05:00:27Z","timestamp":1735189227000},"page":"218-237","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0697-5568","authenticated-orcid":true,"given":"Tsutomu","family":"Shinohara","sequence":"first","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Now with Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Japan (T.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0361-824X","authenticated-orcid":true,"given":"Jan-Renier","family":"Moonen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9871-5244","authenticated-orcid":true,"given":"Yoon Hong","family":"Chun","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Now with Department of Pediatrics, Incheon St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul (Y.H.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9642-9121","authenticated-orcid":true,"given":"Yannick C.","family":"Lee-Yow","sequence":"additional","affiliation":[{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Department of Genetics (Y.C.L.-Y., K.G., J.M.E.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9205-3457","authenticated-orcid":true,"given":"Kenichi","family":"Okamura","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Department of Cardiothoracic Surgery (K.O.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason M.","family":"Szafron","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Now with Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA (J.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2288-2556","authenticated-orcid":true,"given":"Jordan","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiqin","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingli","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Guntur","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Austria (D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalina","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7405-0903","authenticated-orcid":true,"given":"Sarasa","family":"Isobe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Now with the National Defense Medical College, Saitama, Japan (S.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-5012","authenticated-orcid":true,"given":"Melody","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Department of Bioengineering (M.D., A.L.M.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3324-4346","authenticated-orcid":true,"given":"Weiguang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Guo","sequence":"additional","affiliation":[{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Department of Genetics (Y.C.L.-Y., K.G., J.M.E.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin D.","family":"Franco","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine (B.D.F., C.P.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cholawat","family":"Pacharinsak","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine (B.D.F., C.P.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3084-3300","authenticated-orcid":true,"given":"Laura J.","family":"Pisani","sequence":"additional","affiliation":[{"name":"Department of Radiology, Stanford University School of Medicine, CA (L.J.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6911-3351","authenticated-orcid":true,"given":"Shinji","family":"Saitoh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Japan (S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6038-8161","authenticated-orcid":true,"given":"Yoshihide","family":"Mitani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Mie University Graduate School of Medicine, Japan (Y.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1902-171X","authenticated-orcid":true,"given":"Alison L.","family":"Marsden","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., D.G., S.T., S.I., M.D., W.Y., A.L.M., M.R.)"},{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Vera Moulton Wall Center for Pulmonary Vascular Diseases (T.S., J.-R.M., Y.H.C., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., M.R.), Stanford University School of Medicine, CA"},{"name":"Department of Bioengineering (M.D., A.L.M.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5754-1719","authenticated-orcid":true,"given":"Jesse M.","family":"Engreitz","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute (T.S., J.-R.M., Y.H.C., K.O., J.M.S., J. Kaplan, A.C., L.W., S.T., S.I., M.D., A.L.M., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Basic Science and Engineering Initiative, Betty Irene Moore Children\u2019s Heart Center, Lucile Packard Children\u2019s Hospital (T.S., J.-R.M., Y.C.L.-Y., J. Kaplan, A.C., L.W., S.T., S.I., K.G., J.M.E., M.R.), Stanford University School of Medicine, CA"},{"name":"Department of Genetics (Y.C.L.-Y., K.G., J.M.E.), Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5435-7182","authenticated-orcid":true,"given":"Jakob","family":"K\u00f6rbelin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Germany (J. 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