title: In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug.
abstract: We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial endothelial cells (PAECs) from patients who had idiopathic pulmonary arterial hypertension (PAH) in comparison with controls. Because HMGA1 promotes epithelial-to-mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (endothelial-to-mesenchymal transition), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced idiopathic PAH.
  
  
  
  We documented increased HMGA1 in PAECs cultured from idiopathic PAH versus donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to pulmonary arterial endothelium, and identified many cells double-positive for HMGA1 and SM22α in occlusive and plexogenic lesions. Because decreased expression and function of bone morphogenetic protein receptor 2 (BMPR2) is observed in PAH, we reduced BMPR2 by small interfering RNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced platelet endothelial cell adhesion molecule 1 (CD31) and increased endothelial-to-mesenchymal transition markers, αSM actin, SM22α, calponin, phospho-vimentin, and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSM actin was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary endothelial cells from mice with endothelial cell-specific loss of Bmpr2 showed similar gene and protein changes.
  
  
  
  Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Hopper
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Jan-Renier A J
authors.initials: JR
authors.lastname: Moonen
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Isabel
authors.initials: I
authors.lastname: Diebold
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Aiqin
authors.initials: A
authors.lastname: Cao
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Tojais
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Jan K
authors.initials: JK
authors.lastname: Hennigs
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Mingxia
authors.initials: M
authors.lastname: Gu
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
authors.forename: Lingli
authors.initials: L
authors.lastname: Wang
authors.affiliation: From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.). marlener@stanford.edu.
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D025741:HMGA1a Protein / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007223:Infant; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D000071250:Snail Family Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D055815:Young Adult
chemical_list: C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D025741:HMGA1a Protein; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: HMGA1 protein; endothelial-to-mesenchymal transition; hypertension, pulmonary