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.

The aim of this study was to determine whether leukotriene C4 (LTC4) is a mediator of hypoxic pulmonary vasoconstriction. We hypothesized that similar increases in LTC4, detected in the lung parenchyma and pulmonary vascular compartment during cyclooxygenase blockade with indomethacin (INDO), would be observed during an equal increase in pulmonary arterial pressure caused by acute alveolar hypoxia (HYP, 100% N2) or platelet-activating factor (PAF, 10 micrograms into the pulmonary artery). Rat lungs were perfused at constant flow in vitro with an albumin-Krebs-Henseleit solution. Mean pulmonary arterial pressure (n = 6 per group) increased from a base line of 10.9 +/- 1.2 to 15.8 +/- 2.1 (HYP + INDO) and 15.5 +/- 1.9 (SE) Torr (PAF + INDO). LTC4 levels increased only in response to PAF + INDO; perfusate levels increased from 0.4 +/- 0.07 to 5.3 +/- 1.1 ng/40 ml, and lung parenchymal levels increased from 1.9 +/- 0.07 to 22.8 +/- 5.3 ng/lung. Diethylcarbamazine (lipoxygenase inhibitor) reduced PAF-induced lung parenchymal levels of LTC4 by 68% and pulmonary hypertension by 63%. We conclude that 1) LTC4 is not a mediator of hypoxic pulmonary vasoconstriction and 2) intravascular PAF is a potent stimulus for LTC4 production in the lung parenchyma.

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