title: ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease.
abstract: BACKGROUND
  Pulmonary veno-occlusive disease is caused by excessive cell proliferation and fibrosis, which obliterate the lumen of pulmonary venules, leading to pulmonary hypertension, right ventricular failure, and death. This condition has no effective treatment and a 5-year survival of <5%. Understanding the mechanism of this disease and designing effective therapies are urgently needed.
  
  
  RESULTS
  We show that mice with homozygous deletion of the Ets transcription factor Erg die between embryonic day 16.5 and 3 months of age as a result of pulmonary veno-occlusive disease, capillary hemorrhage, and pancytopenia. We demonstrate that Erg binds to and serves as a transcriptional activator of the G-protein-coupled receptor gene Aplnr, the expression of which is uniquely specific for venous endothelium and that knockout of either Erg or Aplnr results in pulmonary venule-specific endothelial proliferation in vitro. We show that mice with either homozygous-global or endothelium-directed deletion of Aplnr manifest pulmonary veno-occlusive disease and right heart failure, detectable at 8 months of age. Levels of pulmonary ERG and APLNR in patients with pulmonary veno-occlusive disease undergoing lung transplantation were significantly lower than those of control subjects.
  
  
  CONCLUSIONS
  Our results suggest that ERG and APLNR are essential for endothelial homeostasis in venules in the lung and that perturbation in ERG-APLNR signaling is crucial for the development of pulmonary veno-occlusive disease. We identify this pathway as a potential therapeutic target for the treatment of this incurable disease.
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Christopher
authors: C
authors: Lathen
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Yu
authors: Y
authors: Zhang
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Jennifer
authors: J
authors: Chow
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Martanday
authors: M
authors: Singh
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Grace
authors: G
authors: Lin
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Vishal
authors: V
authors: Nigam
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Yasser A
authors: YA
authors: Ashraf
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Jason X
authors: JX
authors: Yuan
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.).
authors: Ivan M
authors: IM
authors: Robbins
authors: From the Division of Cardiothoracic Surgery (C.L., Y.Z, J.C., M.S., Y.A.A., P.A.T), Department of Pathology (G.L.), Division of Cardiology (V.N), University of California, San Diego; Department of Medicine, University of Illinois, Chicago (J.X.Y.); and Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, TN (I.M.R.). pthistlethwaite@ucsd.edu.
authors: Patricia A
authors: PA
authors: Thistlethwaite
mesh_terms: D000818:Animals; D000075244:Apelin Receptors; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007763:Lac Operon; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D011651:Pulmonary Artery / Q000473:pathology; D011667:Pulmonary Veins / Q000473:pathology; D011668:Pulmonary Veno-Occlusive Disease / Q000473:pathology* / Q000601:surgery; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; C072312:ERG protein, human; C531115:ERG protein, mouse; D015513:Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG
keywords: hypertension, pulmonary; pulmonary veins; pulmonary veno-occlusive disease