Rationale: Pulmonary veno-occlusive disease (PVOD) is an incurable condition characterised by the progressive remodelling of pulmonary veins, venules and capillaries. The resulting pulmonary hypertension leads to right ventricular hypertrophy, and death within 1-2 years if untreated. Biallelic mutations in the stress sensing kinase, EIF2AK4 (GCN2), are the main genetic cause of PVOD. We hypothesized that loss of GCN2 may lead to a pro-inflammatory phenotype which may be contributing to the development of PVOD.

Results & Conclusions: We modelled PVOD using mice with homozygous null mutations in gcn2. Gcn2^-/- mice spontaneously developed an increase in right ventricular systolic pressure, compared to wild-type controls (28.1[SD 3.4] vs. 24.7[SD 3.7] mmHg, p =0.04). Both left and right ventricles exhibited hypertrophy in the gcn2^-/- mice but left ventricular systolic pressures were normal. Inflammatory cytokines were raised in gcn2^-/- mice at baseline in both serum and lung compartments, which was exaggerated after stimulation with LPS. Preliminary single-cell RNA sequencing analysis of lung cells from gcn2^-/- mice show upregulation of pro-inflammatory pathways. Mice given mitomycin-c also demonstrated ventricular remodelling and increased cytokine production. We have shown, for the first time, that gcn2^-/- mice at baseline reproduce features of PVOD and share a pro-inflammatory phenotype with other forms of pulmonary hypertension. We are now investigating if loss of a key inflammatory cytokine can reverse the pulmonary hypertension in our mouse models. Our scRNA sequencing data will provide us with independent validation of pathways dysregulated by gcn2 loss.