Abstract 10904: Integrins Signaling Represents an Exciting Therapeutic Avenue to Counter Vascular Remodeling and Right Ventricular Failure in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is characterized by progressive obstruction of pulmonary arteries (PAs), culminating in right ventricular (RV) failure and premature death. Like cancer cells, PA smooth muscle cells (PASMCs) isolated from PAH patients exhibit exaggerated proliferation and resistance to apoptosis in response to extracellular matrix remodeling. Integrins, members of the cell adhesion receptors superfamily, are known to promote cell proliferation, survival, hypertrophic growth and fibrosis, which are key elements contributing to PAs remodeling and RV failure. Therefore, we hypothesized that integrins signaling could promote PAH-PASMC proliferation and resistance to apoptosis contributing to PAs vascular remodeling, and RV maladaptive hypertrophy and fibrosis, leading to RV failure. Using NanoString, we found that members of the fibronectin-binding integrin (FiBI) family were the most abundantly expressed in PASMCs and RV fibroblasts (RVFbs) isolated from PAH patients. By western blot (WB), we showed that FiBIs expression is significantly changed in distal PAs, PASMCs, PA endothelial cells and decompensated RV from PAH patients compared to controls (p<0.05). In vitro , pharmacological inhibition of FiBIs decreases PAH-PASMCs proliferation (WB: PLK1; Ki67 labeling; p<0.05, n=5) and resistance to apoptosis (WB: Survivin; Annexin V labeling; p<0.05, n=5). These effects were associated with a decreased activation of FiBIs downstream signaling, FAK and MAPK pathways. In adult rat cardiomyocytes and human RVFbs, FiBIs inhibition decreases phenylephrine-induced hypertrophy (f-actin labeling; p<0.001) and TGFβ1-induced RVFb activation (WB: αSMA, and Col1; p<0.05). In vivo , in both moncrotaline and sugen/hypoxia rats with established PAH, pharmacological inhibition of FiBIs alone or in combination with macitentan and tadalafil improves hemodynamic (mPAP, CO, TAPSE, RVFAC; p<0.05) and vascular remodeling (EVG; p<0.01). In the PA banding rat model, inhibition of FiBIs attenuates RV failure (CO, TAPSE, RVEDP, RVFAC; p<0.01). Our results suggest that integrins play a key role in the pathophysiology of PAH in both the lungs and the RV. Their inhibition provided significant beneficial effects both in vitro and in vivo .