The ERG-APLNR Axis Controls Pulmonary Venule Endothelial Proliferation in Pulmonary Veno-Occlusive Disease
Background—Pulmonary veno-occlusive disease (PVOD) is caused by excessive cell proliferation and fibrosis which obliterates 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 less than 5%. Understanding the mechanism of this disease and designing effective therapies is urgently needed.
Methods and Results—We show that mice with homozygous deletion of the Ets transcription factor, Erg, die between E16.5 and three months of age from PVOD, capillary hemorrhage, and pancytopenia. We demonstrate that Erg binds to and serves as a transcriptional activator of the G-protein-coupled receptor gene, Aplnr, whose expression in the vasculature is uniquely specific for venous endothelium, and that knockout of either Erg or Aplnr results in pulmonary venous-specific endothelial proliferation in vitro. We show that mice with either homozygous-global or endothelial-directed deletion of Aplnr manifest PVOD and right heart failure, detectable at 8 months of age. Levels of pulmonary ERG and APLNR in patients with PVOD undergoing lung transplantation were significantly lower than those of controls.
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 PVOD. We identify this pathway as a potential therapeutic target for the treatment of this incurable disease.
- Received December 16, 2013.
- Revision received July 10, 2014.
- Accepted July 18, 2014.