Pro-proliferative and inflammatory signaling converge on the FoxO1 transcription factor in pulmonary hypertension – a new therapeutic approach

Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that FoxO1 was downregulated (expression) and inactivated (phosphorylation, nuclear exclusion) in vessels/PASMCs of human and experimental PH lungs. This was reproduced by ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in PASMCs reproduced PH features in vitro and in vivo. Pharmacological (intravenous and inhaled Paclitaxel) and gene therapeutic reconstitution of FoxO1 transcriptional activity restored the physiologically quiescent PASMC phenotype in vitro, which was linked to changes in cell cycle control and BMPR2 signaling, and reversed vascular remodeling and right heart hypertrophy in vivo. Thus PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a therapeutic option for PH.