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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(10): 1814-1826
DOI: 10.1055/s-0042-1755329
Atherosclerosis and Ischaemic Disease

Protein Tyrosine Phosphatase 1B Deficiency in Vascular Smooth Muscle Cells Promotes Perivascular Fibrosis following Arterial Injury

Rajinikanth Gogiraju   *
1   Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
,
Sogol Gachkar   *
1   Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
,
David Velmeden   *
1   Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
,
Magdalena L. Bochenek
1   Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
,
Konstantinos Zifkos
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
,
Astrid Hubert
1   Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
,
Thomas Münzel
1   Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
3   German Center for Cardiovascular Research (DZHK), Rhine-Main Site, Mainz, Germany
,
Stefan Offermanns
4   Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5   Centre for Molecular Medicine, Medical Faculty, JW Goethe University Frankfurt, Frankfurt, Germany
6   Cardiopulmonary Institute (CPI), Frankfurt, Germany
7   German Center for Cardiovascular Research (DZHK e.V.), Rhine-Main Site, Frankfurt and Bad Nauheim, Germany
,
Katrin Schäfer 
1   Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
3   German Center for Cardiovascular Research (DZHK), Rhine-Main Site, Mainz, Germany
› Author Affiliations Funding This study was supported by grants from the Deutsche Forschungsgemeinschaft (SCHA 808/15-1 to K.S.) and the German Center for Cardiovascular Research (DZHK e.V.; Doktoranden-Stipendium to D.V.). Results shown in this study are part of the medical thesis of D.V.
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Abstract

Background Smooth muscle cell (SMC) phenotype switching plays a central role during vascular remodeling. Growth factor receptors are negatively regulated by protein tyrosine phosphatases (PTPs), including its prototype PTP1B. Here, we examine how reduction of PTP1B in SMCs affects the vascular remodeling response to injury.

Methods Mice with inducible PTP1B deletion in SMCs (SMC.PTP1B-KO) were generated by crossing mice expressing Cre.ERT2 recombinase under the Myh11 promoter with PTP1Bflox/flox mice and subjected to FeCl3 carotid artery injury.

Results Genetic deletion of PTP1B in SMCs resulted in adventitia enlargement, perivascular SMA+ and PDGFRβ+ myofibroblast expansion, and collagen accumulation following vascular injury. Lineage tracing confirmed the appearance of Myh11-Cre reporter cells in the remodeling adventitia, and SCA1+ CD45- vascular progenitor cells increased. Elevated mRNA expression of transforming growth factor β (TGFβ) signaling components or enzymes involved in extracellular matrix remodeling and TGFβ liberation was seen in injured SMC.PTP1B-KO mouse carotid arteries, and mRNA transcript levels of contractile SMC marker genes were reduced already at baseline. Mechanistically, Cre recombinase (mice) or siRNA (cells)-mediated downregulation of PTP1B or inhibition of ERK1/2 signaling in SMCs resulted in nuclear accumulation of KLF4, a central transcriptional repressor of SMC differentiation, whereas phosphorylation and nuclear translocation of SMAD2 and SMAD3 were reduced. SMAD2 siRNA transfection increased protein levels of PDGFRβ and MYH10 while reducing ERK1/2 phosphorylation, thus phenocopying genetic PTP1B deletion.

Conclusion Chronic reduction of PTP1B in SMCs promotes dedifferentiation, perivascular fibrosis, and adverse remodeling following vascular injury by mechanisms involving an ERK1/2 phosphorylation-driven shift from SMAD2 to KLF4-regulated gene transcription.

Keywords

adventitia - fibrosis - neointima formation - phosphatases - smooth muscle cells

* These authors share the first authorship.


Supplementary Material



Publication History

Received: 15 March 2022

Accepted: 25 June 2022

Article published online:
08 September 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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