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Circulation. 2014 Sep 30;130(14):1179-91. doi: 10.1161/CIRCULATIONAHA.113.007822. Epub 2014 Jul 25.

ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease.

Author information

1
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.).
2
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.

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.

METHODS AND 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.

KEYWORDS:

hypertension, pulmonary; pulmonary veins; pulmonary veno-occlusive disease

PMID:
25062690
PMCID:
PMC4182129
DOI:
10.1161/CIRCULATIONAHA.113.007822
[Indexed for MEDLINE]
Free PMC Article

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