Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension

Abstract

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.

Keywords: collagen; compliance; mechanotransduction; right ventricle; stiffness.

Fig. 1.

Pathogenesis of pulmonary vascular extracellular matrix (ECM) remodeling in pulmonary arterial hypertension (PAH). Increased shear stress from increased flow, hypoxia, inflammation, and altered bone morphogenic protein receptor 2 (BMPR2) signaling causes the endothelial-to-mesenchymal transition (EndoMT), in which endothelial cells acquire a mesenchymal phenotype with increased expression of a gene profile similar to smooth muscle cells. These myofibroblast-like cells cause remodeling of the ECM by increased deposition and cross-linkage of collagen through increased secretion of matrix metalloproteinases (MMPs), metalloproteases [a disintegrin and metalloproteinases (ADAMs)], serine elastases, and lysyl oxidases (LOXs), and decreased secretion of their endogenous inhibitors, like tissue inhibitors of metalloproteinase (TIMPs). HMGA1, high-mobility group AT-hook 1; IRF-1, interferon regulatory factor-1; PAECs, pulmonary artery endothelial cells; ROS, reactive oxygen species; TGF, transforming growth factor.

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.

Fig. 3.

Schematic illustration of the major steps in the development from pulmonary arterial collagen deposition to pulmonary arterial narrowing and potential therapeutic targets for treatment of pulmonary arterial hypertension (PAH). Increased shear stress, increased pulsatility, hypoxia, inflammation, and altered bone morphogenic protein receptor 2 (BMPR2) signaling cause the endothelial-to-mesenchymal transition (EndoMT), which, in turn, leads to remodeling of the extracellular matrix (ECM) and increased vascular stiffness through increased deposition and cross-linkage of collagen and breakdown of elastin. Increased stiffness promotes pulmonary endothelial cell, smooth muscle cell, and fibroblast cell proliferation. This causes pulmonary arterial remodeling with decreased compliance and cross-sectional luminal area leading to elevated pulmonary artery pressure and pulmonary vascular resistance. Potential novel therapeutic targets to treat PAH are presented in red boxes.