Abstract 10717: Role of Integrin Signaling in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by progressive obstruction and decreased compliance of pulmonary arteries (PA), leading to right ventricular (RV) failure and premature death. It is now recognized that, like cancer cells, PA smooth muscle cells (PASMCs) exhibit exaggerated proliferation and resistance to apoptosis in response to increased PA stiffness caused by extracellular matrix (ECM) remodeling. Integrins (members of the cell adhesion receptors superfamily) are known to promote cell proliferation, survival, hypertrophic growth and fibrosis, which are key elements in the progression of PAH. Therefore, we explored integrins expression and its effects on PA remodeling and RV failure. By RNA sequencing, we demonstrated a significant upregulation of integrin signaling pathways. Among all integrins, the fibronectin binding integrin (FiBI) family was the most abundant in PASMCs and RV fibroblasts (RVFbs) isolated from PAH patients (n=5). By western blot (WB) we showed that integrin expression is significantly changed in distal PAs, PASMCs and RV from PAH patients (n=6-8) compared to controls (n=5-8). Similarly, increased expression was found in monocrotaline (MCT) and pulmonary artery banding (PAB) rats (n=20, p<0.05.) In vitro , pharmacological inhibition of FiBI decreases PAH-PASMCs proliferation (WB: PCNA and Ki67 labeling; p<0.05) and resistance to apoptosis (WB: Survivin and Annexin V labeling; p<0.05). These effects were associated with a decreased activation of the AKT/mTOR pathway. In cardiomyocytes and human RVFbs, FiBI inhibition decreased phenylephrine-induced hypertrophy (Phalloidin labeling; p<0.001) and TGFβ1-induced RVFbs activation (WB: αSMA, CTGF, FN and Col1; p<0.05) and proliferation (Ki67; p<0.05). In vivo , pharmacological FiBI inhibition improved PAs remodeling (EVG staining) and RV function (SV, CO, TAPSE, S-Wave, as assessed by echocardiography and right heart catheterization) in MCT rats with established PAH (n=20; p<0.05). We demonstrated that upregulation of fibronectin binding integrins and broad spectrum integrin inhibition resulted in improvements in distal PAs remodeling and RV failure. These results suggest that integrins play an important role in the pathophysiology of PAH.