Pulmonary arterial hypertension (PAH) is characterized by the narrowing of pulmonary arteries (PAs), causing right ventricular (RV) failure and premature death. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients exhibit increased proliferation and resistance to apoptosis in response to extracellular matrix remodeling. Integrins are known to be involved in all these processes. Our hypothesis is that integrin signaling promotes PASMCs proliferation and apoptosis resistance, leading to PA remodeling, RV maladaptive hypertrophy and fibrosis, resulting in RV failure in PAH.

Using NanoString, we identified members of the fibronectin-binding integrins (FnBIs) family as the most abundantly expressed in PAH-PASMCs. We confirmed the changes in FnBIs expression levels by Western blot (WB) in distal PAs, PASMCs and decompensated RVs from PAH patients compared to controls. Pharmacological inhibition of FnBIs decreased PAH-PASMCs proliferation (WB PLK1; Ki67), resistance to apoptosis (WB Survivin; Annexin V) and was associated with a decreased activation of FnBIs downstream signaling pathways FAK and ILK. In adult rat cardiomyocytes and human RV fibroblasts (RVFbs), FnBIs inhibition decreased phenylephrine-induced hypertrophy (f-actin labelling) and TGF?1-induced RVFbs activation (WB ?SMA, COL1). In both monocrotaline and sugen/hypoxia rats, pharmacological inhibition of FnBIs alone or in combination with macitentan and tadalafil improved RV function (mPAP, CO, TAPSE) and vascular remodeling (EVG). In the PA banding rat model, inhibition of FnBIs attenuated RV failure (CO, TAPSE, RVEDP).

In conclusion, FnBIs signaling promotes maladaptive remodeling of the pulmonary vasculature and RV in PAH.