Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by remodeling of the extracellular matrix (ECM) of the pulmonary arteries with increased collagen deposition, cross-linkage of collagen, and breakdown of elastic laminae. Extracellular matrix remodeling occurs due to an imbalance in the proteolytic enzymes, such as matrix metalloproteinases, elastases, and lysyl oxidases, and tissue inhibitor of matrix metalloproteinases, which, in turn, results from endothelial cell dysfunction, endothelial-to-mesenchymal transition, and inflammation. ECM remodeling and pulmonary vascular stiffness occur early in the disease process, before the onset of the increase in the intimal and medial thickness and pulmonary artery pressure, suggesting that the ECM is a cause rather than a consequence of distal pulmonary vascular remodeling. ECM remodeling and increased pulmonary arterial stiffness promote proliferation of pulmonary vascular cells (endothelial cells, smooth muscle cells, and adventitial fibroblasts) through mechanoactivation of various signaling pathways, including transcriptional cofactors YAP/TAZ, transforming growth factor-β, transient receptor potential channels, Toll-like receptor, and NF-κB. Inhibition of ECM remodeling and mechanotransduction prevents and reverses experimental pulmonary hypertension. These data support a central role for ECM remodeling in the pathogenesis of the PAH, making it an attractive novel therapeutic target.