Abstract 4139371: Treatment of pulmonary arterial hypertension by blocking integrin a5b1, a potential disease-modifying strategy

Introduction: Pulmonary arterial hypertension (PAH) is marked by pathological remodeling of distal arteries, driven by hyperplasia of pulmonary arterial smooth muscle cells (PASMCs), dysfunction of pulmonary arterial endothelial cells (PAECs), and increased deposition of the extracellular matrix (ECM). Hypothesis: Considering the crucial role of ECM in vascular restructuring, we investigated the potential of therapeutically targeting a5b1, a fibronectin-binding integrin involved in cell proliferation and angiogenesis, for PAH treatment. Aim: To evaluate the therapeutic potential of targeting a5b1 for the treatment of PAH. Methods: We have developed potent, orally bioavailable small molecule inhibitors (SMis) and monoclonal antibodies (mAbs) targeting a5b1 to evaluate its therapeutic potential. The effect of a5b1 inhibition was assessed in cultured PASMCs, human precision-cut lung slices (PCLS), and a rat Sugen/hypoxia PAH model. Results: PAH patients exhibited increased expression of fibronectin and a5b1 in distal pulmonary arteries. Selective inhibition of a5b1 in cultured PASMCs modulated multiple pathways involved in cell cycle regulation at both transcriptional and post-transcriptional levels, thereby blocking cellular proliferation. PCLS treated with a5b1 inhibitors showed decreased expression of pathways involved in ECM deposition and reduced levels of smooth muscle cell markers. In the rat Sugen/hypoxia PAH model, a5b1 inhibition with either an SMi or mAb significantly improved cardiac and vascular function by reducing pulmonary arterial wall thickness, right ventricular hypertrophy, and fibrosis. Cardiac improvement is further evidenced by a reduction in circulating NT-proBNP and NT-proANP levels. Conclusion: These findings reveal a previously underappreciated role for a5b1 in PAH pathogenesis and support the potential of a5b1 inhibition as a disease-modifying therapeutic strategy for managing PAH.