Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently

Waard, Vivian de; Bot, Ilze; Jager, Saskia C.A. de; Talib, Sara; Egashira, Kensuke; Vries, Margreet R. de; Quax, Paul H.A.; Biessen, Erik A. L.; Berkel, Theo J.C. Van

doi:10.1016/j.atherosclerosis.2010.01.042

Cited by 46 publications

(42 citation statements)

References 22 publications

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“…In contrast, the highest MCP-1 signal was detected in the aortic media. Thbs1 gene deficiency did not alter the medial MCP-1 accumulation nor apoptosis of vascular SMCs (data not shown), two well-established processes resulting from aneurysm induction 44, 45, 55, 56 .…”

Section: Discussionmentioning

confidence: 87%

“…Transmural infiltration of inflammatory cells, predominantly macrophages, is a major histological characteristic of aneurysm 5, 17, 42, 45 . Elastase- or CaPO 4 -induced aneurysmal tissues harvested from Thbs1 +/+ mice displayed a significant infiltration of monocytes and macrophages, consistent with features of the models as reported in previous literature 6, 46 (Figure 2C, D and Supplemental Figure VC).…”

Section: Resultsmentioning

confidence: 99%

“…For example, MCP-1 production by injured SMCs has been shown to be important for aneurysm-associated inflammation 55, 73, 74 . However, knocking out MCP-1 (also called CCL2) has limited impact on aneurysm development, whereas knocking out its receptor, CCR2, significantly reduces aneurysm expansion 42, 45, 73 , indicating a more complex role for CCL1/CCR2 signaling in aneurysm development. The co-localization between TSP1 accumulation and macrophages suggests that the elevated TSP1 is likely a result of inflammatory cell recruitment (i.e.…”

Section: Discussionmentioning

confidence: 99%

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Thrombospondin-1 (TSP1) Contributes to the Development of Vascular Inflammation by Regulating Monocytic Cell Motility in Mouse Models of Abdominal Aortic Aneurysm

Liu

Morgan

Ren

et al. 2015

Circulation Research

114

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Rationale Histological examination of abdominal aortic aneurysm (AAA) tissues demonstrates extracellular matrix (ECM) destruction and infiltration of inflammatory cells. Previous work with mouse models of AAA has shown that anti-inflammatory strategies can effectively attenuate aneurysm formation. Thrombospondin-1 (TSP1) is a matricellular protein involved in the maintenance of vascular structure and homeostasis through the regulation of biological functions such as cell proliferation, apoptosis, and adhesion. Expression levels of TSP1 correlate with vascular disease conditions. Objective To use TSP1 deficient (Thbs1−/−) mice to test the hypothesis that TSP1 contributes to pathogenesis of AAAs. Methods and Results Mouse experimental AAA was induced either through perivascular treatment with calcium phosphate, intraluminal perfusion with porcine elastase, or systemic administration of Angiotensin II. Induction of AAA increased TSP1 expression in aortas of C57BL/6 or apoE−/− mice. Compared to Thbs1+/+ mice, Thbs1−/− mice developed significantly smaller aortic expansion when subjected to AAA inductions, which was associated with diminished infiltration of macrophages. Thbs1−/− monocytic cells had reduced adhesion and migratory capacity in vitro compared to wildtype counterparts. Adoptive transfer of Thbs1+/+ monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1−/− mice. Conclusions TSP1 expression plays a significant role in regulation of migration and adhesion of mononuclear cells, contributing to vascular inflammation during AAA development.

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Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Thrombospondin-1 (TSP1) Contributes to the Development of Vascular Inflammation by Regulating Monocytic Cell Motility in Mouse Models of Abdominal Aortic Aneurysm

Liu

Morgan

Ren

et al. 2015

Circulation Research

114

View full text Add to dashboard Cite

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“…In particular, Ccr2 −/− but not Ccr2 +/+ bone marrow transplantation into ApoE3-leiden mice reduced the size of atherosclerotic lesions; moreover, overexpression of Ccl2 on hematopoietic cells in ApoE −/− mice increased atherosclerotic lesion size (Aiello et al 1999; Guo et al 2003). However, blockade of Ccr2 by either 7ND treatment or Ccr2 −/− bone marrow transplantation did not affect the progression of established atherosclerotic lesion development (de Waard V et al 2010; Guo et al 2005). Further studies in mice showed that Ccr2 deficiency abolished the egress of monocytes from the bone marrow and markedly reduced Ccl2-induced recruitment of monocytes from the blood into inflammatory sites (Boring et al 1997; Tacke et al 2007; Tsou et al 2007).…”

Section: The Chemokine System As An Immunoregulator In Atherogenesismentioning

confidence: 87%

Regulation of Atherogenesis by Chemokines and Chemokine Receptors

Wan

Murphy

2012

Arch. Immunol. Ther. Exp.

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Atherosclerosis is a chronic inflammatory and metabolic disorder affecting large and medium-sized arteries, and the leading cause of mortality worldwide. The pathogenesis of atherosclerosis involves accumulation of lipids and leukocytes in the intima of blood vessel walls creating plaque. How leukocytes accumulate in plaque remains poorly understood, however chemokines acting at specific G protein-coupled receptors appear to be important. Studies using knockout mice suggest that chemokine receptor signaling may either promote or inhibit atherogenesis, depending on the receptor. These proof of concept studies have spurred efforts to develop drugs targeting the chemokine system in atherosclerosis, and several have shown beneficial effects in animal models. This article will review key discoveries in basic and translational research in this area.

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“…Chemokine receptor polymorphisms, such as CCR2 heterozygote V64l and CCR5 delta 32 deletion, are also associated with increased AAA disease risk 17, 18 . In experimental models, increased CCL2 and CCL5 mRNA and/or protein expression is present in aneurysmal aortic tissue 19–23 , and either leukocyte CCR2-gene deletion, or siRNA-mediated expression knockdown attenuates AAA development 24–29 . While the significance of CCL2/CCR2 interaction in AAA pathogenesis is well described, the role of CCL5/CCR5 remains controversial and uncertain 25 .…”

Section: Introductionmentioning

confidence: 99%

Peptide Inhibitor of CXCL4–CCL5 Heterodimer Formation, MKEY, Inhibits Experimental Aortic Aneurysm Initiation and Progression

Iida

Xuan

et al. 2013

ATVB

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Objective Macrophages are critical contributors in abdominal aortic aneurysm (AAA) disease. We examined the ability of MKEY, a peptide inhibitor of CXCL4-CCL5 interaction, to influence AAA progression in murine models. Methods and Results AAAs were created in 10-week-old male C57BL/6 mice by transient infrarenal aortic porcine pancreatic elastase (PPE) infusion. Mice were treated with MKEY via intravenous injection either 1) before PPE infusion, or 2) after aneurysm initiation. Immunostaining demonstrated CCL5 and CCR5 expression on aneurysmal aortae and mural monocytes/macrophages, respectively. MKEY treatment partially inhibited transmural AAA migration of adaptively transferred leukocytes in recipient mice. While all vehicle-pretreated mice developed AAA, aneurysms formed in only 60% (3/5) and 14% (1/7) of mice pretreated with MKEY at 10 and 20 mg /kg, respectively. MKEY pretreatment reduced aortic diameter enlargement, preserved medial elastin fibers and smooth muscle cells, and attenuated mural macrophage infiltration, angiogenesis, and aortic MMP2 & 9 expression following PPE infusion. MKEY initiated after PPE infusion also stabilized and/or reduced enlargement of existing AAAs. Finally, MKEY treatment was effective in limiting AAA formation following angiotensin II infusion in apolipoprotein E deficient mice. Conclusion MKEY suppresses AAA formation and progression in two complementary experimental models. Peptide inhibition of CXCL4-CCL5 interactions may represent a viable translational strategy to limit progression of human AAA disease.

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Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently

Cited by 46 publications

References 22 publications

Thrombospondin-1 (TSP1) Contributes to the Development of Vascular Inflammation by Regulating Monocytic Cell Motility in Mouse Models of Abdominal Aortic Aneurysm

Thrombospondin-1 (TSP1) Contributes to the Development of Vascular Inflammation by Regulating Monocytic Cell Motility in Mouse Models of Abdominal Aortic Aneurysm

Regulation of Atherogenesis by Chemokines and Chemokine Receptors

Peptide Inhibitor of CXCL4–CCL5 Heterodimer Formation, MKEY, Inhibits Experimental Aortic Aneurysm Initiation and Progression

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