{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:40:29Z","timestamp":1785426029596,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,15]]},"group-title":"Cell Biology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["NHLBI R01HL158841"],"award-info":[{"award-number":["NHLBI R01HL158841"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NHLBI R01HL174007"],"award-info":[{"award-number":["NHLBI R01HL174007"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NHLBI T32HL160517"],"award-info":[{"award-number":["NHLBI T32HL160517"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NIGMS P30GM145500"],"award-info":[{"award-number":["NIGMS P30GM145500"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NIGMS P20GM103652"],"award-info":[{"award-number":["NIGMS P20GM103652"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Genome-wide association studies have identified rare and common mutations associated with increased risk of pulmonary arterial hypertension (PAH), but the mechanism by which impaired SOX17 expression increases PAH risk is not known. Notably, SOX17 plays a critical role in endothelial identity during development by suppressing RUNX1 through binding to its promoter and directing stem and progenitor cells toward an endothelial rather than a hematopoietic cell fate. RUNX1 functions as a key regulator of myeloid differentiation, aberrant angiogenesis and adverse cardiac remodeling. Previously, we found that RUNX1 inhibition reverses pulmonary hypertension (PH) in multiple animal models. Here, we hypothesize that impaired expression of SOX17 in PAH leads to endothelial cell (EC) dysfunction by failing to suppress RUNX1.<\/jats:p>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>Human pulmonary artery endothelial cells (HPAECs) with stable SOX17 CRISPR\/Cas9 knockout or RUNX1 overexpression were generated and examined for endothelial and hematopoietic gene expression, proliferation, migration, apoptosis, and angiogenesis. Immortalized lymphoblastoid cell lines (LCLs) from PAH patients with SOX17 mutations and healthy controls were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into ECs. The effect of RUNX1 inhibition on Sugen\/hypoxia-PH was examined in rats, SOX17 enhancer knockout (SOX17enhKO) mice, and Cdh5-CreERT2;Runx1(flox\/flox);SOX17enhKO triple transgenic mice. SOX17 and RUNX1 expression were analyzed in peripheral blood samples from PAH patients (n=359).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>HPAECs with SOX17 deletion or RUNX1 overexpression exhibited decreased expression of EC markers, enhanced proliferation and migration, defective angiogenesis, and decreased apoptosis. RUNX1 siRNA knockdown or RUNX1 inhibition by Ro5-3335 partially restored the endothelial properties in SOX17 KO HPAECs. ECs differentiated from SOX17 mutant PAH patient iPSCs exhibited upregulated RUNX1 expression and loss of endothelial identity, which was also partially restored by RUNX1 siRNA or Ro5-3335. In addition, SOX17enhKO mice had increased RUNX1 expression and susceptibility to Sugen\/hypoxia-induced PH (SuHx-PH). Treatment with RUNX1 inhibitors or inducible endothelial-specific deletion of RUNX1 rescued SuHx-PH susceptibility in SOX17enhKO mice. RUNX1 inhibitors Ro5-3335 and Ro24-7429 also reversed SuHx-PH in wild-type rats. In addition, plasma RUNX1 expression was higher in PAH patients lacking detectable SOX17 expression than in patients with detectable SOX17 expression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>Impaired SOX17 expression increases the risk of PAH through insufficient suppression of RUNX1, leading to pulmonary endothelial dysfunction. RUNX1 inhibition mitigates PH associated with SOX17 deficiency and may represent a novel therapeutic strategy for PAH, especially those with rare or common SOX17 mutations.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.14.725187","type":"posted-content","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T14:55:24Z","timestamp":1778856924000},"source":"Crossref","is-referenced-by-count":0,"title":["Impaired SOX17 Expression Causes Endothelial Dysfunction and Pulmonary Arterial Hypertension by Insufficient Suppression of RUNX1"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6571-546X","authenticated-orcid":false,"given":"Bedia","family":"Akosman","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moon Jung","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamini","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Pereira","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Eun","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eui Young","family":"So","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allyson Sherman","family":"Roe","sequence":"additional","affiliation":[{"name":"Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8058-3004","authenticated-orcid":false,"given":"Navneet","family":"Singh","sequence":"additional","affiliation":[{"name":"Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony M.","family":"Reginato","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey E.","family":"Ventetuolo","sequence":"additional","affiliation":[{"name":"Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R.","family":"Wilkins","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Rhodes","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Klinger","sequence":"additional","affiliation":[{"name":"Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Rhode Island Hospital, The Warren Alpert Medical 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