Pulmonary arterial Hypertension (PAH) is characterized by vasoconstriction and remodeling of pulmonary arteries (PAs), causing right ventricular (RV) failure, and premature death. Extensive proliferation of PA smooth muscle cells (PASMCs) is perhaps the most prominent feature of PAH accounting for the histopathological changes seen in this disease. With this recognition, direct targeting of vascular remodeling by anti-proliferative approaches provides a promising strategy that holds the potential to reverse the remodeling process.

To discover novel actionable targets implicated in vascular remodeling, we performed a comparative RNA-sequencing analysis between control and PAH-PASMCs. To extract reliable targets, we next enriched our own experiment with publicly available datasets conducted on comparable cell lines. Among the genes that were concordantly up-regulated in PAH-PASMCs, we identified aurora kinase B (AURKB), a druggable target that plays a critical role in the success of mitosis. Further experiments revealed that FOXM1 positively regulates AURKB and that pharmacological (Barasertib) and molecular inhibition of AURKB significantly reduce PAH-PASMC proliferation (EdU & Ki67 labelling, PLK1 expression) and survival (Annexin V labelling, Survivin expression). These effects were associated with mitotic defects, including chromosome misalignment, resulting in multinucleated cells. In vivo, treatment with Barasertib significantly reduced pulmonary vascular remodeling, improved hemodynamics and decreased RV hypertrophy in monocrotaline-injected rats with established PAH.

To sum up, we demonstrated that the up-regulation of AURKB contributes to vascular remodeling in PAH and represents a new therapeutic target.