Thromb Haemost 2021; 121(11): 1530-1540
DOI: 10.1055/a-1397-1858
Atherosclerosis and Ischaemic Disease

Deficiency of Endothelial CD40 Induces a Stable Plaque Phenotype and Limits Inflammatory Cell Recruitment to Atherosclerotic Lesions in Mice

Mark Colin Gissler
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Philipp Scherrer
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Nathaly Anto-Michel
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Jan Pennig
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Natalie Hoppe
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Lisa Füner
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Carmen Härdtner
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Peter Stachon
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Xiaowei Li
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Lucia Sol Mitre
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Timoteo Marchini
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Josef Madl
2  Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Germany
,
Carolin Wadle
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Ingo Hilgendorf
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Constantin von zur Mühlen
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Christoph Bode
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Christian Weber*
3  Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
4  German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
5  Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
Esther Lutgens
3  Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
4  German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
6  Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands
,
Dennis Wolf
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Norbert Gerdes
7  Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
,
Andreas Zirlik
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
8  Division of Cardiology, Medical University of Graz, Graz, Austria
,
Florian Willecke
1  Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
9  Klinik für Allgemeine und Interventionelle Kardiologie/Angiologie, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bochum, Germany
› Author Affiliations
Funding This work was supported by a research grant of the German Research Foundation (DFG) to A. Z. (Project-ID: 366904753), the German Center for Cardiovascular Research (DZHK) to C. W. and A. Z. (Project-ID: 81X2800139), and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program to D. W. (Project-ID: 853425). F. W. was supported by a research grant of the Forschungskomission of the University of Freiburg. M. C. G. was supported by a MOTI-VATE scholarship (Else Kröner-Fresenius-Stiftung) and a Kaltenbach scholarship of the Deutsche Herzstiftung. D. W. was supported by a fellowship from the Berta-Ottenstein-Program for Advanced Clinician Scientists at the Faculty of Medicine, University of Freiburg.

Abstract

Objectives The co-stimulatory CD40L–CD40 dyad exerts a critical role in atherosclerosis by modulating leukocyte accumulation into developing atherosclerotic plaques. The requirement for cell-type specific expression of both molecules, however, remains elusive. Here, we evaluate the contribution of CD40 expressed on endothelial cells (ECs) in a mouse model of atherosclerosis.

Methods and Results Atherosclerotic plaques of apolipoprotein E-deficient (Apoe −/− ) mice and humans displayed increased expression of CD40 on ECs compared with controls. To interrogate the role of CD40 on ECs in atherosclerosis, we induced EC-specific (BmxCreERT2-driven) deficiency of CD40 in Apoe −/− mice. After feeding a chow diet for 25 weeks, EC-specific deletion of CD40 (iEC-CD40) ameliorated plaque lipid deposition and lesional macrophage accumulation but increased intimal smooth muscle cell and collagen content, while atherosclerotic lesion size did not change. Leukocyte adhesion to the vessel wall was impaired in iEC-CD40-deficient mice as demonstrated by intravital microscopy. In accord, expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in the vascular endothelium declined after deletion of CD40. In vitro, antibody-mediated inhibition of human endothelial CD40 significantly abated monocyte adhesion on ECs.

Conclusion Endothelial deficiency of CD40 in mice promotes structural features associated with a stable plaque phenotype in humans and decreases leukocyte adhesion. These results suggest that endothelial-expressed CD40 contributes to inflammatory cell migration and consecutive plaque formation in atherogenesis.

* The review process for this paper was fully handled by Gregory Y. H. Lip, Editor-in-Chief.


Supplementary Material



Publication History

Received: 07 March 2020

Accepted: 13 February 2021

Publication Date:
22 February 2021 (online)

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany