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Article

Proteoglycan 4 Modulates Osteogenic Smooth Muscle Cell Differentiation during Vascular Remodeling and Intimal Calcification

by
Till Seime
1,
Asim Cengiz Akbulut
2,
Moritz Lindquist Liljeqvist
1,
Antti Siika
1,
Hong Jin
1,3,
Greg Winski
3,
Rick H. van Gorp
2,
Eva Karlöf
1,
Mariette Lengquist
1,
Andrew J. Buckler
1,
Malin Kronqvist
1,
Olivia J. Waring
4,
Jan H. N. Lindeman
5,
Erik A. L. Biessen
4,
Lars Maegdefessel
3,6,
Anton Razuvaev
1,
Leon J. Schurgers
2,7,
Ulf Hedin
1,† and
Ljubica Matic
1,*,†
1
Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17164 Stockholm, Sweden
2
Department of Biochemistry, CARIM, Maastricht University, 6229 ER Maastricht, The Netherlands
3
Department of Medicine, Karolinska Institutet, 17164 Stockholm, Sweden
4
Department of Pathology, CARIM, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
5
Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
6
Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technische Universität München, 81679 Munich, Germany
7
Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 52062 Aachen, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2021, 10(6), 1276; https://doi.org/10.3390/cells10061276
Submission received: 25 April 2021 / Revised: 16 May 2021 / Accepted: 18 May 2021 / Published: 21 May 2021
(This article belongs to the Section Cells of the Cardiovascular System)
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Abstract

Calcification is a prominent feature of late-stage atherosclerosis, but the mechanisms driving this process are unclear. Using a biobank of carotid endarterectomies, we recently showed that Proteoglycan 4 (PRG4) is a key molecular signature of calcified plaques, expressed in smooth muscle cell (SMC) rich regions. Here, we aimed to unravel the PRG4 role in vascular remodeling and intimal calcification. PRG4 expression in human carotid endarterectomies correlated with calcification assessed by preoperative computed tomographies. PRG4 localized to SMCs in early intimal thickening, while in advanced lesions it was found in the extracellular matrix, surrounding macro-calcifications. In experimental models, Prg4 was upregulated in SMCs from partially ligated ApoE−/− mice and rat carotid intimal hyperplasia, correlating with osteogenic markers and TGFb1. Furthermore, PRG4 was enriched in cells positive for chondrogenic marker SOX9 and around plaque calcifications in ApoE−/− mice on warfarin. In vitro, PRG4 was induced in SMCs by IFNg, TGFb1 and calcifying medium, while SMC markers were repressed under calcifying conditions. Silencing experiments showed that PRG4 expression was driven by transcription factors SMAD3 and SOX9. Functionally, the addition of recombinant human PRG4 increased ectopic SMC calcification, while arresting cell migration and proliferation. Mechanistically, it suppressed endogenous PRG4, SMAD3 and SOX9, and restored SMC markers’ expression. PRG4 modulates SMC function and osteogenic phenotype during intimal remodeling and macro-calcification in response to TGFb1 signaling, SMAD3 and SOX9 activation. The effects of PRG4 on SMC phenotype and calcification suggest its role in atherosclerotic plaque stability, warranting further investigations.
Keywords: Proteoglycan 4; smooth muscle cells; atherosclerosis; extracellular matrix; vascular remodeling; calcification Proteoglycan 4; smooth muscle cells; atherosclerosis; extracellular matrix; vascular remodeling; calcification

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MDPI and ACS Style

Seime, T.; Akbulut, A.C.; Liljeqvist, M.L.; Siika, A.; Jin, H.; Winski, G.; van Gorp, R.H.; Karlöf, E.; Lengquist, M.; Buckler, A.J.; et al. Proteoglycan 4 Modulates Osteogenic Smooth Muscle Cell Differentiation during Vascular Remodeling and Intimal Calcification. Cells 2021, 10, 1276. https://doi.org/10.3390/cells10061276

AMA Style

Seime T, Akbulut AC, Liljeqvist ML, Siika A, Jin H, Winski G, van Gorp RH, Karlöf E, Lengquist M, Buckler AJ, et al. Proteoglycan 4 Modulates Osteogenic Smooth Muscle Cell Differentiation during Vascular Remodeling and Intimal Calcification. Cells. 2021; 10(6):1276. https://doi.org/10.3390/cells10061276

Chicago/Turabian Style

Seime, Till, Asim Cengiz Akbulut, Moritz Lindquist Liljeqvist, Antti Siika, Hong Jin, Greg Winski, Rick H. van Gorp, Eva Karlöf, Mariette Lengquist, Andrew J. Buckler, and et al. 2021. "Proteoglycan 4 Modulates Osteogenic Smooth Muscle Cell Differentiation during Vascular Remodeling and Intimal Calcification" Cells 10, no. 6: 1276. https://doi.org/10.3390/cells10061276

APA Style

Seime, T., Akbulut, A. C., Liljeqvist, M. L., Siika, A., Jin, H., Winski, G., van Gorp, R. H., Karlöf, E., Lengquist, M., Buckler, A. J., Kronqvist, M., Waring, O. J., Lindeman, J. H. N., Biessen, E. A. L., Maegdefessel, L., Razuvaev, A., Schurgers, L. J., Hedin, U., & Matic, L. (2021). Proteoglycan 4 Modulates Osteogenic Smooth Muscle Cell Differentiation during Vascular Remodeling and Intimal Calcification. Cells, 10(6), 1276. https://doi.org/10.3390/cells10061276

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