Published Online
on April 30, 2007

A more recent version of this article appeared on May 15, 2007

This Article Full Text (PDF) Data Supplement All Versions of this Article: 115/19/2516    most recent CIRCULATIONAHA.106.660472v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bot, I. Articles by Biessen, E. A.L. Search for Related Content PubMed PubMed Citation Articles by Bot, I. Articles by Biessen, E. A.L. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Carotid Artery Disease Hazardous Substances DB CROMOLYN Related Collections Apoptosis Pathophysiology Mechanism of atherosclerosis/growth factors

Submitted on August 24, 2006
Accepted on March 2, 2007

Perivascular Mast Cells Promote Atherogenesis and Induce Plaque Destabilization in Apolipoprotein E-Deficient Mice

Ilze Bot PhD^*, Saskia C.A. de Jager BSc, Alma Zernecke MD, PhD, Ken A. Lindstedt PhD, Theo J.C. van Berkel PhD, Christian Weber MD, PhD, and Erik A.L. Biessen PhD

From the Division of Biopharmaceutics (I.B., S.C.A.d.J., T.J.C.v.B., E.A.L.B.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, the Netherlands; Institute of Molecular Cardiovascular Research (A.Z., C.W.), University Hospital, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; Wihuri Research Institute (K.A.L.), Helsinki, Finland.

^* To whom correspondence should be addressed. E-mail: i.bot{at}lacdr.leidenuniv.nl.

Background--Mast cells are major effector cells in allergy and host defense responses. Their increased number and state of activation in perivascular tissue during atherosclerosis may point to a role in cardiovascular disorders. In the present study, we investigated the contribution of perivascular mast cells to atherogenesis and plaque stability in apolipoprotein E-deficient mice.

Methods and Results--We show here that episodes of systemic mast cell activation during plaque progression in mice leads to robust plaque expansion. Targeted activation of perivascular mast cells in advanced plaques sharply increases the incidence of intraplaque hemorrhage, macrophage apoptosis, vascular leakage, and CXCR2/VLA-4-mediated recruitment of leukocytes to the plaque. Importantly, treatment with the mast cell stabilizer cromolyn does prevent all the adverse phenomena elicited by mast cell activation.

Conclusions--This is the first study to demonstrate that mast cells play a crucial role in plaque progression and destabilization in vivo. We propose that mast cell stabilization could be a new therapeutic approach to the prevention of acute coronary syndromes.

Key words: apoptosis • atherosclerosis • hemorrhage • inflammation • mast cells

This article has been cited by other articles:

				P. Libby, P. M. Ridker, G. K. Hansson, and for the Leducq Transatlantic Network on Atherothro Inflammation in Atherosclerosis From Pathophysiology to Practice. J. Am. Coll. Cardiol., December 1, 2009; 54(23): 2129 - 2138. [Abstract] [Full Text] [PDF]

				M. Takaoka, D. Nagata, S. Kihara, I. Shimomura, Y. Kimura, Y. Tabata, Y. Saito, R. Nagai, and M. Sata Periadventitial Adipose Tissue Plays a Critical Role in Vascular Remodeling Circ. Res., October 23, 2009; 105(9): 906 - 911. [Abstract] [Full Text] [PDF]

				J. C. Sluimer, F. D. Kolodgie, A. P.J.J. Bijnens, K. Maxfield, E. Pacheco, B. Kutys, H. Duimel, P. M. Frederik, V. W.M. van Hinsbergh, R. Virmani, et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage. J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1517 - 1527. [Abstract] [Full Text] [PDF]

				S. F. Mause and C. Weber Intrusion through the fragile back door immature plaque microvessels as entry portals for leukocytes and erythrocytes in atherosclerosis. J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1528 - 1531. [Full Text] [PDF]

				T. Tsuruda, J. Kato, K. Hatakeyama, K. Kojima, M. Yano, Y. Yano, K. Nakamura, F. Nakamura-Uchiyama, Y. Matsushima, T. Imamura, et al. Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm Circ. Res., June 6, 2008; 102(11): 1368 - 1377. [Abstract] [Full Text] [PDF]

				H. Loppnow, K. Werdan, and M. Buerke Invited review: Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms Innate Immunity, April 1, 2008; 14(2): 63 - 87. [Abstract] [PDF]

				H. M. Heikkila, S. Latti, M. J. Leskinen, J. K. Hakala, P. T. Kovanen, and K. A. Lindstedt Activated Mast Cells Induce Endothelial Cell Apoptosis by a Combined Action of Chymase and Tumor Necrosis Factor-{alpha} Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 309 - 314. [Abstract] [Full Text] [PDF]

				M. Nachtigal, A. Ghaffar, and E. P. Mayer Galectin-3 Gene Inactivation Reduces Atherosclerotic Lesions and Adventitial Inflammation in ApoE-Deficient Mice Am. J. Pathol., January 1, 2008; 172(1): 247 - 255. [Abstract] [Full Text] [PDF]

				P. Libby and G.-P. Shi Mast Cells as Mediators and Modulators of Atherogenesis Circulation, May 15, 2007; 115(19): 2471 - 2473. [Full Text] [PDF]