Journal article
PAI-1 deficiency drives pulmonary vascular smooth muscle remodeling and pulmonary hypertension
American journal of physiology. Lung cellular and molecular physiology, v 327(3), pp L319-L326
01 Sep 2024
PMID: 38860847
Abstract
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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Details
- Title
- PAI-1 deficiency drives pulmonary vascular smooth muscle remodeling and pulmonary hypertension
- Creators
- Tatiana V Kudryashova - University of PittsburghSergei V Zaitsev - Children's Hospital of PhiladelphiaLifeng Jiang - University of California, DavisBenjamin J Buckley - University of WollongongJoshua P McGuckin - Drexel UniversityDmitry Goncharov - University of California, DavisIryna Zhyvylo - University of California, DavisDerek Lin - University of California, DavisGeoffrey Newcomb - Lung InstituteBryce Piper - Lung InstituteSrimathi Bogamuwa - Lung InstituteAisha Saiyed - University of California, DavisLeyla Teos - University of California, DavisAndressa Pena - University of PittsburghMarie Ranson - University of WollongongJohn R Greenland - University of California, San FranciscoPaul J Wolters - University of California, San FranciscoMichael J Kelso - University of WollongongMortimer Poncz - Children's Hospital of PhiladelphiaHorace M DeLisser - University of PennsylvaniaDouglas B Cines - University of PennsylvaniaElena A Goncharova - University of California, DavisLaszlo Farkas - Lung InstituteVictoria Stepanova (Corresponding Author) - University of Pennsylvania
- Publication Details
- American journal of physiology. Lung cellular and molecular physiology, v 327(3), pp L319-L326
- Publisher
- American Physiological Society (APS)
- Grant note
- R01 HL166932 / NHLBI NIH HHS R01HL150638 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) Nina Ireland Program for Lung Health / UCSF | Department of Medicine, University of California, San Francisco (UCSF Department of Medicine) R01 HL130261 / NHLBI NIH HHS R01HL166932 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) RO1HL141462 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) Cardiovascular Medical Research and Education Fund (CMREF) TS150032 / DOD | USA | MEDCOM | MRDC | U.S. Army Medical Research Acquisition Activity (USAMRAA) R01 HL159256 / NHLBI NIH HHS R35HL150698 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering and Science
- Web of Science ID
- WOS:001313861200002
- Scopus ID
- 2-s2.0-85201839799
- Other Identifier
- 991022202505304721