Abstract
BACKGROUND: The mechanism of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) remains poorly understood. Fibulin 5, a multifunctional extracellular matrix protein, was reinduced in balloon-injured vessels and may contribute to vascular remodelling. This study aimed to investigate the role and molecular mechanism of action of fibulin 5 in the pathogenesis of CHD-PAH. METHODS & RESULTS: We found elevated fibulin 5 expression in pulmonary artery smooth muscle cells (PASMCs) from CHD-PAH patients and shunt-induced PAH rats. In vivo, downregulation of fibulin-5 expression by intratracheally delivered adeno-associated viral vectors prevents shunt-associated PAH and associated pulmonary artery remodeling. In vitro, fibulin 5 expression in human PASMCs (hPASMCs) was changed through transduction with lentiviruses. We found fibulin 5 overexpression enhanced TGF-β1-induced proliferation and migration, as assessed by EdU, cell count, and transwell assays. Western blotting showed altered expression of contractile and synthetic phenotype markers. These effects were reversed by the PI3K/AKT inhibitor LY294002, suggesting fibulin 5 acts through the TGF-β1/PI3K/AKT pathway. CONCLUSIONS: Overall, our data provide new insights into the influence of fibulin 5 on the modification of hPASMC dysfunction and pulmonary artery remodelling in shunt-associated PAH.