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

journal contribution
posted on 2024-11-17, 15:03 authored by Tatiana V Kudryashova, Sergei V Zaitsev, Lifeng Jiang, Benjamin J Buckley, Joshua P McGuckin, Dmitry Goncharov, Iryna Zhyvylo, Derek Lin, Geoffrey Newcomb, Bryce Piper, Srimathi Bogamuwa, Aisha Saiyed, Leyla Teos, Andressa Pena, Marie Ranson, John R Greenland, Paul J Wolters, Michael J Kelso, Mortimer Poncz, Horace M DeLisser, Douglas B Cines, Elena A Goncharova, Laszlo Farkas, Victoria Stepanova
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: 1) 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; 2) PAI-1-/- mice spontaneously develop pulmonary vascular remodeling associated with upregulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and 3) 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.NEW & NOTEWORTHY 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.

Funding

National Heart, Lung, and Blood Institute (R01 HL130261)

History

Journal title

American journal of physiology. Lung cellular and molecular physiology

Volume

327

Issue

3

Pagination

L319-L326

Language

English

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