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PAI-1 deficiency drives pulmonary vascular smooth muscle remodeling and pulmonary hypertension
Journal article   Open access   Peer reviewed

PAI-1 deficiency drives pulmonary vascular smooth muscle remodeling and pulmonary hypertension

Tatiana V Kudryashova, Sergei V Zaitsev, Lifeng Jiang, Benjamin J Buckley, Joshua P McGuckin, Dmitry Goncharov, Iryna Zhyvylo, Derek Lin, Geoffrey Newcomb, Bryce Piper, …
American journal of physiology. Lung cellular and molecular physiology, v 327(3), pp L319-L326
01 Sep 2024
DOI: https://doi.org/10.1152/ajplung.00110.2024
PMID: 38860847
url
https://pmc.ncbi.nlm.nih.gov/articles/PMC11444499/View
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Abstract

Animals Cell Proliferation Endothelial Cells - metabolism Endothelial Cells - pathology Humans Hypertension, Pulmonary - metabolism Hypertension, Pulmonary - pathology Hypertrophy, Right Ventricular - metabolism Hypertrophy, Right Ventricular - pathology Hypertrophy, Right Ventricular - physiopathology Male Mechanistic Target of Rapamycin Complex 1 - metabolism Mice Mice, Inbred C57BL Mice, Knockout Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Plasminogen Activator Inhibitor 1 - genetics Plasminogen Activator Inhibitor 1 - metabolism Plasminogen Activator Inhibitor 2 - genetics Plasminogen Activator Inhibitor 2 - metabolism Pulmonary Artery - metabolism Pulmonary Artery - pathology Urokinase-Type Plasminogen Activator - genetics Urokinase-Type Plasminogen Activator - metabolism Vascular Remodeling Apoptosis Signal Transduction
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) are the primary physiological inhibitors of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but their roles in PAH are unsettled. Here, we report that: ) PAI-1, but not PAI-2, is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared with controls; ) PAI-1 mice spontaneously develop pulmonary vascular remodeling associated with upregulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and ) pharmacological inhibition of uPA in human PAH PASMCs suppresses proproliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation, and induces apoptosis in vitro, and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in vivo in mice. These data strongly suggest that downregulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent upregulation of mTOR and transforming growth factor-β (TGF-β) signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH. This study identifies a novel role for the deficiency of plasminogen activator inhibitor (PAI)-1 and resultant unrestricted uPA activity in PASMC remodeling and PH in vitro and in vivo, provides novel mechanistic link from PAI-1 loss through uPA-induced Akt/mTOR and TGFβ-Smad3 upregulation to pulmonary vascular remodeling in PH, and suggests that inhibition of uPA to rebalance the uPA-PAI-1 tandem might provide a novel approach to complement current therapies used to mitigate this pulmonary vascular disease.

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