Fig. 2.

Pulmonary vascular extracellular matrix (ECM) stiffness induces pulmonary vascular remodeling. Stiff ECM activates yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling in pulmonary artery endothelial cells (PAECs), pulmonary artery smooth muscle cells (PASMCs), and pulmonary adventitial fibroblasts (PAFs) through mechanotransduction. Activation of YAP/TAZ signaling causes increased proliferation of PAECs and PASMCs through three different mechanisms: increased glutaminolysis and anaplerosis, upregulation of microRNA-21/27, and increased secretion of IL-6, endothelin, and fibroblast growth factor (FGF). In addition, stiff ECM increases PAEC proliferation by activating transforming growth factor (TGF)-β signaling, transient receptor potential channels (TRPCs), and Toll-like receptors (TLRs) as well as the NF-κB signaling axis through mechanotransduction. Finally, activation of YAP/TAZ signaling, in turn, leads to increased deposition of ECM by PAECs, PASMCs, and PAFs by upregulation of microRNA-130/301, leading to a feedback loop of increased ECM stiffness and mechanotransduction. ApoE, apolipoprotein E; CSA, cross-sectional area; LOX, lysyl oxidase; LRP8, LDL receptor-related protein 8; PAH, pulmonary arterial hypertension; PPARγ, peroxisome proliferator-activated receptor-γ; PVR, pulmonary vascular resistance.