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We hypothesized that cAbl is downactivated in experimental and human PAH, thus leading to reduced DNA integrity and angiogenic capacity of pulmonary ECs from patients with PAH (PAH-ECs). We found cAbl and phosphorylated cAbl concentrations to be lower in the endothelium of remodeled pulmonary vessels in the lungs of patients with PAH than in control subjects. Similar observations were obtained for the lungs of Sugen\u2009+\u2009hypoxia and monocrotaline rats with established pulmonary hypertension. These in situ abnormalities were also replicated in vitro, with cultured PAH-ECs displaying lower cAbl expression and activity and an altered DNA damage response and capacity of tube formation. Downregulation of cAbl by RNA interference in control ECs or its inhibition with dasatinib resulted in genomic instability and the failure to form tubes, whereas upregulation of cAbl with 5-(1,3-diaryl-1H-pyrazol-4-yl) hydantoin reduced DNA damage and apoptosis in PAH-ECs. Finally, we establish the existence of cross-talk between cAbl and bone morphogenetic protein receptor type II. This work identifies the loss of cAbl signaling as a novel contributor to pulmonary EC dysfunction associated with PAH.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0332oc","type":"journal-article","created":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T09:56:46Z","timestamp":1652435806000},"page":"215-226","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":10,"title":["Loss of cAbl Tyrosine Kinase in Pulmonary Arterial Hypertension Causes Dysfunction of Vascular Endothelial Cells"],"prefix":"10.1093","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5987-0268","authenticated-orcid":false,"given":"Benjamin","family":"Le Vely","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, UMR_S 999, Hypertension Pulmonaire: Pathophysiologie et Innovation Th\u00e9rapeutique, H\u00f4pital Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"Universit\u00e9 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