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

Christopher Lathen, Yu Zhang, Y. Jennifer Chow, Martanday Singh, Grace Lin, Vishal Nigam, Yasser A. Ashraf, Jason Yuan, Ivan M. Robbins, Patricia A. Thistlethwaite

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1179-1191
Number of pages13
JournalCirculation
Volume130
Issue number14
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Pulmonary Veno-Occlusive Disease
Venules
Lung
Endothelium
Proto-Oncogene Proteins c-ets
Pancytopenia
Lung Transplantation
Therapeutics
G-Protein-Coupled Receptors
Pulmonary Hypertension
Homeostasis
Fibrosis
Heart Failure
Cell Proliferation
Hemorrhage
Gene Expression
Survival

Keywords

  • Hypertension, pulmonary
  • Pulmonary veins
  • Pulmonary veno-occlusive disease

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Lathen, C., Zhang, Y., Chow, Y. J., Singh, M., Lin, G., Nigam, V., ... Thistlethwaite, P. A. (2014). ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease. Circulation, 130(14), 1179-1191. https://doi.org/10.1161/CIRCULATIONAHA.113.007822

ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease. / Lathen, Christopher; Zhang, Yu; Chow, Y. Jennifer; Singh, Martanday; Lin, Grace; Nigam, Vishal; Ashraf, Yasser A.; Yuan, Jason; Robbins, Ivan M.; Thistlethwaite, Patricia A.

In: Circulation, Vol. 130, No. 14, 2014, p. 1179-1191.

Research output: Contribution to journalArticle

Lathen, C, Zhang, Y, Chow, YJ, Singh, M, Lin, G, Nigam, V, Ashraf, YA, Yuan, J, Robbins, IM & Thistlethwaite, PA 2014, 'ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease', Circulation, vol. 130, no. 14, pp. 1179-1191. https://doi.org/10.1161/CIRCULATIONAHA.113.007822
Lathen, Christopher ; Zhang, Yu ; Chow, Y. Jennifer ; Singh, Martanday ; Lin, Grace ; Nigam, Vishal ; Ashraf, Yasser A. ; Yuan, Jason ; Robbins, Ivan M. ; Thistlethwaite, Patricia A. / ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease. In: Circulation. 2014 ; Vol. 130, No. 14. pp. 1179-1191.
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AU - Lathen, Christopher

AU - Zhang, Yu

AU - Chow, Y. Jennifer

AU - Singh, Martanday

AU - Lin, Grace

AU - Nigam, Vishal

AU - Ashraf, Yasser A.

AU - Yuan, Jason

AU - Robbins, Ivan M.

AU - Thistlethwaite, Patricia A.

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N2 - 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.

AB - 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.

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