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Although a phenotypic switch in pulmonary endothelial cells (ECs) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal of this study was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. A bioinfomatics approach, patient samples, and in vitro experiments were used. By combining a metaanalysis of human idiopathic PAH (iPAH)-associated gene-expression microarrays and a unique gene expression-profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from patients with iPAH and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control because excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified breast cancer 1 (BRCA1) as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency\u2013associated loss of DNA damage control.<\/jats:p>","DOI":"10.1165\/rcmb.2013-0349oc","type":"journal-article","created":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T16:16:46Z","timestamp":1401639406000},"page":"1118-1128","source":"Crossref","is-referenced-by-count":78,"title":["Loss of Bone Morphogenetic Protein Receptor 2 Is Associated with Abnormal DNA Repair in Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"50","author":[{"given":"Molong","family":"Li","sequence":"first","affiliation":[{"name":"The Johns Hopkins University School of Medicine, Baltimore, Maryland"},{"name":"Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanna","family":"Vattulainen","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital Helsinki, 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