Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring, Yvonne; Noels, Heidi; Vorst, Emiel P. C. van der; Neideck, Carlos; Egea, Virginia; Drechsler, Maik; Mandl, Manuela; Pawig, Lukas; Jansen, Yvonne; Schröder, Katrin; Bidzhekov, Kiril; Megens, Remco T. A.; Theelen, Wendy; Klinkhammer, Barbara M.; Boor, Peter; Schurgers, Leon J.; Gorp, Rick H. van; Ries, Christian; Kusters, Pascal; Wal, Allard C. van der; Hackeng, Tilman M.; Gäbel, Gábor; Brandes, Ralf P.; Soehnlein, Oliver; Lutgens, Esther; Vestweber, Dietmar; Teupser, Daniel; Holdt, Lesca M.; Rader, Daniel J.; Saleheen, Danish; Weber, Christian

doi:10.1161/circulationaha.117.027646

Cited by 147 publications

(162 citation statements)

References 50 publications

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“…We did not directly demonstrate how endothelial CXCR4 is associated with monocyte recruitment in atherosclerosis. However, based on the literature that reendothelialization of arteries, endothelial proliferation (39), and reduced atherosclerosis (21) is linked to CXCR4 expression and function, we argue that CXCR4 itself has a protective role. Additional recent RNA sequencing data analysis of locally regenerating ECs to recover from endothelial injury in vivo shows enhancement of CXCR4 expression (45).…”

Section: Discussionmentioning

confidence: 82%

“…5B). Since CXCR4 blocking or endothelial specific CXCR4 deficiency was earlier reported to enhance Evans Blue leakage from aortic arches (21), this colocalization likely reflects a compensatory attempt of the endothelium to combat elevated permeability.…”

Section: Cxcr4 Expression In Atherosclerotic Lesions Marks Sites Whermentioning

confidence: 80%

“…Considering that CXCR4 locus in human has been reported to be as a key determinant in coronary heart disease (21) these new findings underscore the possibility that CXCR4-targeted PET tracers or perhaps the 64 Cu-DOTA-vMIP-II tracer may report critical information about plaque status in a clinical setting.…”

Section: Introductionmentioning

confidence: 76%

“…Additional recent RNA sequencing data analysis of locally regenerating ECs to recover from endothelial injury in vivo shows enhancement of CXCR4 expression (45). Endothelial CXCR4 is also reported to be athero-protective through attenuating vascular permeability by enhancing VE-cadherin expression and stabilizing VE-cadherin complexes (21). However, despite its likely protective functional role, the induction of its expression is known to be a consequence of endothelial injury (39) and thus its expression correlates with active plaque.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, vascular permeability is known to be increased at atherosclerotic lesions (29,30). Endothelial CXCR4 attenuates vascular permeability through enhancement of VEcadherin expression and stabilization of junctional VE-cadherin complexes (21). Therefore, we wondered whether endothelial CXCR4 expression is upregulated to compensate for enhanced vascular permeability at atherosclerotic lesions.…”

Section: Cxcr4 Expression In Atherosclerotic Lesions Marks Sites Whermentioning

confidence: 99%

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CXCR4-binding PET tracers link monocyte recruitment and endothelial injury in murine atherosclerosis

Randolph¹,

Elvington²,

Baba

et al. 2020

Preprint

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Viral macrophage inflammatory protein 2 (vMIP-II/vCCL2) binds to multiple chemokine receptors, and vMIP-II based PET tracer ( 64 Cu-DOTA-vMIP-II: vMIP-II tracer) accumulates at atherosclerotic lesions in mice. The magnitude of 64 Cu-DOTA-vMIP-II accumulation correlated with monocyte recruitment, as Apoe -/mice treated with AAV-mApoE showed PET signal declining as monocyte recruitment subsided. Unexpectedly, monocytes themselves were not the major target of the 64 Cu-DOTA-vMIP-II tracer.Using fluorescence-tagged vMIP-II tracer, competitive receptor blocking with CXCR4 antagonists, CXCR4-specific tracer 64 Cu-DOTA-FC131, or CXCR4 staining during disease progression and regression, endothelial cell expression of CXCR4 proved to be the main target of 64 Cu-DOTA-vMIP-II imaging. Expression of CXCR4 was low in nonplaque areas, but strongly detected on endothelium at the edges of progressing plaques, corresponding to a population of proliferating endothelium and to the location in plaques where monocyte recruitment occurred. Thus, endothelial injury status of plaques is marked by CXCR4 expression and that this injury correlates with the tendency of such plaques to recruit monocytes. Furthermore, our findings suggest PET tracers that, through binding CXCR4, may be useful to monitor plaque injury status.

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Section: Discussionmentioning

confidence: 82%

Section: Cxcr4 Expression In Atherosclerotic Lesions Marks Sites Whermentioning

confidence: 80%

Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Cxcr4 Expression In Atherosclerotic Lesions Marks Sites Whermentioning

confidence: 99%

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CXCR4-binding PET tracers link monocyte recruitment and endothelial injury in murine atherosclerosis

Randolph¹,

Elvington²,

Baba

et al. 2020

Preprint

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Decidual CXCR4⁺CD56^brightNK cells as a novel NK subset in maternal–foetal immune tolerance to alleviate early pregnancy failure

Zhang

et al. 2021

Clinical & Translational Med

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Natural killer (NK) cells preferentially accumulate at maternal–foetal interface and are believed to play vital immune‐modulatory roles during early pregnancy and related immunological dysfunction may result in pregnant failure such as recurrent miscarriage (RM). However, the mechanisms underlying the establishment of maternal–foetal immunotolerance are complex but clarifying the roles of decidual NK (dNK) cells offers the potential to design immunotherapeutic strategies to assist RM patients. In this report, we analysed RNA sequencing on peripheral NK (pNK) and decidual NK cells during early pregnancy; we identified an immunomodulatory dNK subset CXCR4 + CD56 bright dNK and investigated its origin and phenotypic and functional characteristics. CXCR4 + CD56 bright dNK displayed a less activated and cytotoxic phenotype but an enhanced immunomodulatory potential relative to the CXCR4 negative subset. CXCR4 + CD56 bright dNK promote Th2 shift in an IL‐4‐dependent manner and can be recruited from peripheral blood and reprogramed by trophoblasts, as an active participant in the establishment of immune‐tolerance during early pregnancy. Diminished CXCR4 + dNK cells and their impaired ability to induce Th2 differentiation were found in RM patients and mouse models of spontaneous abortion. Moreover, adoptive transfer of CXCR4 + dNK cells to NK‐deficient (Nfil3 –/–) mice showed great therapeutic potential of CXCR4 + dNK via recovering the Th2/Th1 bias and reducing embryo resorption rates. The identification of this new dNK cell subset may lay the foundation for understanding NK cell mechanisms in early pregnancy and provide potential prognostic factors for the diagnosis and therapy of RM.

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CXCR4/CXCL12 axis: “old” pathway as “novel” target for anti‐inflammatory drug discovery

Lu,

Li,

Jiang

et al. 2024

Medicinal Research Reviews

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Inflammation is the body's defense response to exogenous or endogenous stimuli, involving complex regulatory mechanisms. Discovering anti‐inflammatory drugs with both effectiveness and long‐term use safety is still the direction of researchers' efforts. The inflammatory pathway was initially identified to be involved in tumor metastasis and HIV infection. However, research in recent years has proved that the CXC chemokine receptor type 4 (CXCR4)/CXC motif chemokine ligand 12 (CXCL12) axis plays a critical role in the upstream of the inflammatory pathway due to its chemotaxis to inflammatory cells. Blocking the chemotaxis of inflammatory cells by CXCL12 at the inflammatory site may block and alleviate the inflammatory response. Therefore, developing CXCR4 antagonists has become a novel strategy for anti‐inflammatory therapy. This review aimed to systematically summarize and analyze the mechanisms of action of the CXCR4/CXCL12 axis in more than 20 inflammatory diseases, highlighting its crucial role in inflammation. Additionally, the anti‐inflammatory activities of CXCR4 antagonists were discussed. The findings might help generate new perspectives for developing anti‐inflammatory drugs targeting the CXCR4/CXCL12 axis.

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Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Cited by 147 publications

References 50 publications

CXCR4-binding PET tracers link monocyte recruitment and endothelial injury in murine atherosclerosis

CXCR4-binding PET tracers link monocyte recruitment and endothelial injury in murine atherosclerosis

Decidual CXCR4⁺CD56^brightNK cells as a novel NK subset in maternal–foetal immune tolerance to alleviate early pregnancy failure

CXCR4/CXCL12 axis: “old” pathway as “novel” target for anti‐inflammatory drug discovery

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Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Cited by 147 publications

References 50 publications

CXCR4-binding PET tracers link monocyte recruitment and endothelial injury in murine atherosclerosis

CXCR4-binding PET tracers link monocyte recruitment and endothelial injury in murine atherosclerosis

Decidual CXCR4+CD56brightNK cells as a novel NK subset in maternal–foetal immune tolerance to alleviate early pregnancy failure

CXCR4/CXCL12 axis: “old” pathway as “novel” target for anti‐inflammatory drug discovery

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Decidual CXCR4⁺CD56^brightNK cells as a novel NK subset in maternal–foetal immune tolerance to alleviate early pregnancy failure