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PAI-1 deficiency drives pulmonary vascular smooth muscle remodeling and pulmonary hypertension.
Kudryashova, Tatiana V; Zaitsev, Sergei V; Jiang, Lifeng; Buckley, Benjamin J; McGuckin, Joshua P; Goncharov, Dmitry; Zhyvylo, Iryna; Lin, Derek; Newcomb, Geoffrey; Piper, Bryce; Bogamuwa, Srimathi; Saiyed, Aisha; Teos, Leyla; Pena, Andressa; Ranson, Marie; Greenland, John R; Wolters, Paul J; Kelso, Michael J; Poncz, Mortimer; DeLisser, Horace M; Cines, Douglas B; Goncharova, Elena A; Farkas, Laszlo; Stepanova, Victoria.
Afiliación
  • Kudryashova TV; University of Pittsburgh Heart, Blood, and Vascular Medicine Institute, Pittsburgh, Pennsylvania, United States.
  • Zaitsev SV; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
  • Jiang L; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
  • Buckley BJ; Department of Internal Medicine, University of California, Davis, California, United States.
  • McGuckin JP; School of Chemistry and Molecular Bioscience and Molecular Horizons Institute, University of Wollongong, Wollongong, New South Wales, Australia.
  • Goncharov D; School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, United States.
  • Zhyvylo I; Department of Internal Medicine, University of California, Davis, California, United States.
  • Lin D; Department of Internal Medicine, University of California, Davis, California, United States.
  • Newcomb G; Department of Internal Medicine, University of California, Davis, California, United States.
  • Piper B; Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, Ohio, United States.
  • Bogamuwa S; Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, Ohio, United States.
  • Saiyed A; Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, Ohio, United States.
  • Teos L; Department of Internal Medicine, University of California, Davis, California, United States.
  • Pena A; Department of Internal Medicine, University of California, Davis, California, United States.
  • Ranson M; University of Pittsburgh Heart, Blood, and Vascular Medicine Institute, Pittsburgh, Pennsylvania, United States.
  • Greenland JR; School of Chemistry and Molecular Bioscience and Molecular Horizons Institute, University of Wollongong, Wollongong, New South Wales, Australia.
  • Wolters PJ; School of Medicine, University of California, San Francisco, California, United States.
  • Kelso MJ; San Francisco Veterans Affairs Health Care System, San Francisco, California, United States.
  • Poncz M; School of Medicine, University of California, San Francisco, California, United States.
  • DeLisser HM; School of Chemistry and Molecular Bioscience and Molecular Horizons Institute, University of Wollongong, Wollongong, New South Wales, Australia.
  • Cines DB; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
  • Goncharova EA; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
  • Farkas L; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
  • Stepanova V; Department of Internal Medicine, University of California, Davis, California, United States.
Am J Physiol Lung Cell Mol Physiol ; 327(3): L319-L326, 2024 Sep 01.
Article en En | MEDLINE | ID: mdl-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 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-ß (TGF-ß) 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 TGFß-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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidor 1 de Activador Plasminogénico / Remodelación Vascular / Hipertensión Pulmonar / Músculo Liso Vascular Límite: Animals / Humans / Male Idioma: En Revista: Am J Physiol Lung Cell Mol Physiol Asunto de la revista: BIOLOGIA MOLECULAR / FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidor 1 de Activador Plasminogénico / Remodelación Vascular / Hipertensión Pulmonar / Músculo Liso Vascular Límite: Animals / Humans / Male Idioma: En Revista: Am J Physiol Lung Cell Mol Physiol Asunto de la revista: BIOLOGIA MOLECULAR / FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos