Mast cells participate in smooth muscle cell reprogramming and atherosclerotic plaque calcification

Nikolaos T. Skenteris; Esmeralda Hemme; Lucie Delfos; Glykeria Karadimou; Eva Karlof; Mariette Lengquist; Malin Kronqvist; Xiang Zhang; Lars Maegdefessel; Leon J. Schurgers; Hildur Arnardottir; Erik A. L. Biessen; Ilze Bot; Ljubica Matic

doi:10.1016/j.vph.2023.107167

Mast cells participate in smooth muscle cell reprogramming and atherosclerotic plaque calcification

Nikolaos T. Skenteris, Esmeralda Hemme, Lucie Delfos, Glykeria Karadimou, Eva Karlof, Mariette Lengquist, Malin Kronqvist, Xiang Zhang, Lars Maegdefessel, Leon J. Schurgers, Hildur Arnardottir, Erik A. L. Biessen, Ilze Bot, Ljubica Matic^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Calcification, a key feature of advanced human atherosclerosis, is positively associated with vascular disease burden and adverse events. We showed that macrocalcification can be a stabilizing factor for carotid plaque molecular biology, due to inverse association with immune processes. Mast cells (MCs) are important contributors to plaque instability, but their relationship with macrocalcification is unexplored. With a hypothesis that MC activation negatively associates with carotid plaque macrocalcification, we aimed to investigate the link between MCs and carotid plaque vulnerability, and study MC role in plaque calcification via smooth muscle cells (SMCs).Methods: Pre-operative computed tomography angiographies of patients (n = 40) undergoing surgery for carotid stenosis were used to characterize plaque morphology. Plaque microarrays (n = 40 and n = 126) were used for bioinformatic deconvolution of immune cell populations. Tissue microarrays (n = 103) were used to histologi-cally validate the contribution of activated and resting MCs in plaques. Results: Activated MCs and their typical markers were negatively correlated with macrocalcification. The ratio of activated vs. resting MCs was increased in low-calcified plaques from symptomatic patients. There was no modulating effect of medication on MC ratios. In vitro experiments showed that SMC calcification attenuated MC activation, while both active and resting MCs stimulated SMC calcification and induced dedifferentiation towards a pro-inflammatory-, osteochondrocyte-like phenotype, without modulating their migro-proliferative function.Conclusions: Integrative analyses from human plaques showed that MC activation is inversely associated with macrocalcification and positively with parameters of plaque vulnerability. Mechanistically, MCs induce SMC osteogenic reprograming, while matrix calcification in turn attenuates MC activation, offering new therapeutic avenues for exploration.

Original language	English
Article number	107167
Number of pages	13
Journal	Vascular Pharmacology
Volume	150
Issue number	1
DOIs	https://doi.org/10.1016/j.vph.2023.107167
Publication status	Published - 1 Jun 2023

Keywords

Atherosclerotic plaques
Mast cells
Smooth muscle cells
Intimal calcification
Biobank of Karolinska endarterectomy (BiKE)
MYOCARDIAL-INFARCTION
SHOULDER REGION
DOWN-REGULATION
UP-REGULATION
INFLAMMATION
EXPRESSION
STENOSIS
ENDARTERECTOMY
TRANSITION
TRYPTASE

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Skenteris, N. T., Hemme, E., Delfos, L., Karadimou, G., Karlof, E., Lengquist, M., Kronqvist, M., Zhang, X., Maegdefessel, L., Schurgers, L. J., Arnardottir, H., Biessen, E. A. L., Bot, I., & Matic, L. (2023). Mast cells participate in smooth muscle cell reprogramming and atherosclerotic plaque calcification. Vascular Pharmacology, 150(1), Article 107167. https://doi.org/10.1016/j.vph.2023.107167

@article{ac7eb8bec1744ceaabd4f89a97807d09,

title = "Mast cells participate in smooth muscle cell reprogramming and atherosclerotic plaque calcification",

abstract = "Background: Calcification, a key feature of advanced human atherosclerosis, is positively associated with vascular disease burden and adverse events. We showed that macrocalcification can be a stabilizing factor for carotid plaque molecular biology, due to inverse association with immune processes. Mast cells (MCs) are important contributors to plaque instability, but their relationship with macrocalcification is unexplored. With a hypothesis that MC activation negatively associates with carotid plaque macrocalcification, we aimed to investigate the link between MCs and carotid plaque vulnerability, and study MC role in plaque calcification via smooth muscle cells (SMCs).Methods: Pre-operative computed tomography angiographies of patients (n = 40) undergoing surgery for carotid stenosis were used to characterize plaque morphology. Plaque microarrays (n = 40 and n = 126) were used for bioinformatic deconvolution of immune cell populations. Tissue microarrays (n = 103) were used to histologi-cally validate the contribution of activated and resting MCs in plaques. Results: Activated MCs and their typical markers were negatively correlated with macrocalcification. The ratio of activated vs. resting MCs was increased in low-calcified plaques from symptomatic patients. There was no modulating effect of medication on MC ratios. In vitro experiments showed that SMC calcification attenuated MC activation, while both active and resting MCs stimulated SMC calcification and induced dedifferentiation towards a pro-inflammatory-, osteochondrocyte-like phenotype, without modulating their migro-proliferative function.Conclusions: Integrative analyses from human plaques showed that MC activation is inversely associated with macrocalcification and positively with parameters of plaque vulnerability. Mechanistically, MCs induce SMC osteogenic reprograming, while matrix calcification in turn attenuates MC activation, offering new therapeutic avenues for exploration.",

keywords = "Atherosclerotic plaques, Mast cells, Smooth muscle cells, Intimal calcification, Biobank of Karolinska endarterectomy (BiKE), MYOCARDIAL-INFARCTION, SHOULDER REGION, DOWN-REGULATION, UP-REGULATION, INFLAMMATION, EXPRESSION, STENOSIS, ENDARTERECTOMY, TRANSITION, TRYPTASE",

author = "Skenteris, {Nikolaos T.} and Esmeralda Hemme and Lucie Delfos and Glykeria Karadimou and Eva Karlof and Mariette Lengquist and Malin Kronqvist and Xiang Zhang and Lars Maegdefessel and Schurgers, {Leon J.} and Hildur Arnardottir and Biessen, {Erik A. L.} and Ilze Bot and Ljubica Matic",

year = "2023",

month = jun,

day = "1",

doi = "10.1016/j.vph.2023.107167",

language = "English",

volume = "150",

journal = "Vascular Pharmacology",

issn = "1537-1891",

publisher = "Elsevier Science",

number = "1",

}

Skenteris, NT, Hemme, E, Delfos, L, Karadimou, G, Karlof, E, Lengquist, M, Kronqvist, M, Zhang, X, Maegdefessel, L, Schurgers, LJ, Arnardottir, H, Biessen, EAL, Bot, I & Matic, L 2023, 'Mast cells participate in smooth muscle cell reprogramming and atherosclerotic plaque calcification', Vascular Pharmacology, vol. 150, no. 1, 107167. https://doi.org/10.1016/j.vph.2023.107167

TY - JOUR

T1 - Mast cells participate in smooth muscle cell reprogramming and atherosclerotic plaque calcification

AU - Skenteris, Nikolaos T.

AU - Hemme, Esmeralda

AU - Delfos, Lucie

AU - Karadimou, Glykeria

AU - Karlof, Eva

AU - Lengquist, Mariette

AU - Kronqvist, Malin

AU - Zhang, Xiang

AU - Maegdefessel, Lars

AU - Schurgers, Leon J.

AU - Arnardottir, Hildur

AU - Biessen, Erik A. L.

AU - Bot, Ilze

AU - Matic, Ljubica

PY - 2023/6/1

Y1 - 2023/6/1

N2 - Background: Calcification, a key feature of advanced human atherosclerosis, is positively associated with vascular disease burden and adverse events. We showed that macrocalcification can be a stabilizing factor for carotid plaque molecular biology, due to inverse association with immune processes. Mast cells (MCs) are important contributors to plaque instability, but their relationship with macrocalcification is unexplored. With a hypothesis that MC activation negatively associates with carotid plaque macrocalcification, we aimed to investigate the link between MCs and carotid plaque vulnerability, and study MC role in plaque calcification via smooth muscle cells (SMCs).Methods: Pre-operative computed tomography angiographies of patients (n = 40) undergoing surgery for carotid stenosis were used to characterize plaque morphology. Plaque microarrays (n = 40 and n = 126) were used for bioinformatic deconvolution of immune cell populations. Tissue microarrays (n = 103) were used to histologi-cally validate the contribution of activated and resting MCs in plaques. Results: Activated MCs and their typical markers were negatively correlated with macrocalcification. The ratio of activated vs. resting MCs was increased in low-calcified plaques from symptomatic patients. There was no modulating effect of medication on MC ratios. In vitro experiments showed that SMC calcification attenuated MC activation, while both active and resting MCs stimulated SMC calcification and induced dedifferentiation towards a pro-inflammatory-, osteochondrocyte-like phenotype, without modulating their migro-proliferative function.Conclusions: Integrative analyses from human plaques showed that MC activation is inversely associated with macrocalcification and positively with parameters of plaque vulnerability. Mechanistically, MCs induce SMC osteogenic reprograming, while matrix calcification in turn attenuates MC activation, offering new therapeutic avenues for exploration.

AB - Background: Calcification, a key feature of advanced human atherosclerosis, is positively associated with vascular disease burden and adverse events. We showed that macrocalcification can be a stabilizing factor for carotid plaque molecular biology, due to inverse association with immune processes. Mast cells (MCs) are important contributors to plaque instability, but their relationship with macrocalcification is unexplored. With a hypothesis that MC activation negatively associates with carotid plaque macrocalcification, we aimed to investigate the link between MCs and carotid plaque vulnerability, and study MC role in plaque calcification via smooth muscle cells (SMCs).Methods: Pre-operative computed tomography angiographies of patients (n = 40) undergoing surgery for carotid stenosis were used to characterize plaque morphology. Plaque microarrays (n = 40 and n = 126) were used for bioinformatic deconvolution of immune cell populations. Tissue microarrays (n = 103) were used to histologi-cally validate the contribution of activated and resting MCs in plaques. Results: Activated MCs and their typical markers were negatively correlated with macrocalcification. The ratio of activated vs. resting MCs was increased in low-calcified plaques from symptomatic patients. There was no modulating effect of medication on MC ratios. In vitro experiments showed that SMC calcification attenuated MC activation, while both active and resting MCs stimulated SMC calcification and induced dedifferentiation towards a pro-inflammatory-, osteochondrocyte-like phenotype, without modulating their migro-proliferative function.Conclusions: Integrative analyses from human plaques showed that MC activation is inversely associated with macrocalcification and positively with parameters of plaque vulnerability. Mechanistically, MCs induce SMC osteogenic reprograming, while matrix calcification in turn attenuates MC activation, offering new therapeutic avenues for exploration.

KW - Atherosclerotic plaques

KW - Mast cells

KW - Smooth muscle cells

KW - Intimal calcification

KW - Biobank of Karolinska endarterectomy (BiKE)

KW - MYOCARDIAL-INFARCTION

KW - SHOULDER REGION

KW - DOWN-REGULATION

KW - UP-REGULATION

KW - INFLAMMATION

KW - EXPRESSION

KW - STENOSIS

KW - ENDARTERECTOMY

KW - TRANSITION

KW - TRYPTASE

U2 - 10.1016/j.vph.2023.107167

DO - 10.1016/j.vph.2023.107167

M3 - Article

SN - 1537-1891

VL - 150

JO - Vascular Pharmacology

JF - Vascular Pharmacology

IS - 1

M1 - 107167

ER -