Dataset Information

Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility.

ABSTRACT:

Background

Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte-derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated.

Methods and results

Hematopoietic Hck/Fgr-deficient, LDLr(-/-) chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as the most prominent features. Despite a Ly6C(high)-skewed proinflammatory monocyte phenotype, Hck/Fgr deficiency led to disrupted adhesion of myeloid cells to and transmigration across endothelial monolayers in vitro and atherosclerotic plaques in vivo, as assessed by intravital microscopy, flow cytometry, and histological examination of atherosclerotic arteries. Moreover, Hck/Fgr-deficient macrophages showed blunted podosome formation and mesenchymal migration capacity. In consequence, transmigrated double-knockout macrophages were seen to accumulate in the fibrous cap, potentially promoting its focal erosion, as observed for double-knockout chimeras.

Conclusions

The hematopoietic deficiency of Hck and Fgr led to attenuated atherosclerotic plaque formation by abrogating endothelial adhesion and transmigration; paradoxically, it also promoted plaque instability by causing monocyte subset imbalance and subendothelial accumulation, raising a note of caution regarding src kinase-targeted intervention in plaque inflammation.

SUBMITTER: Medina I

PROVIDER: S-EPMC4535360 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Publications

Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility.

Medina Indira I Cougoule Céline C Drechsler Maik M Bermudez Beatriz B Koenen Rory R RR Sluimer Judith J Wolfs Ine I Döring Yvonne Y Herias Veronica V Gijbels Marjon M Bot Ilze I de Jager Saskia S Weber Christian C Cleutjens Jack J van Berkel Theo J C TJC Sikkink Kees-Jan KJ Mócsai Atilla A Maridonneau-Parini Isabelle I Soehnlein Oliver O Biessen Erik A L EAL

Circulation 20150611 6

<h4>Background</h4>Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte-derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated.<h4>Methods and results</h4>Hematopoietic Hck/Fgr-deficient, LDLr(-/-) chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage c ...[more]

PMID: 26068045

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Project description:Objective: The current antiangiogenic therapy for atherosclerotic plaques was mainly achieved by the use of antiangiogenic drugs, but serious side effects have limited the clinical application. The present study investigated whether therapeutic ultrasound (TUS) treatment with appropriate pressure could selectively deplete the neovasculature in vulnerable plaques to improve its stability with no side effects on the body; the underlying mechanisms were also explored. Methods and Results: A mouse model of advanced atherosclerosis was generated by maintaining apolipoprotein E-deficient (ApoE-/-) mice on a hypercholesterolemic diet (HCD). Plaque, skeletal muscle, mesentery and skin tissue from 114 atheroma-bearing mice were subjected to sham therapy, an ultrasound application combined with microbubbles at four different ultrasound pressures (1.0, 2.0, 3.0, 5.0 MPa), or ultrasound at 5.0 MPa alone. Microvessel density (MVD) was assessed by immunofluorescence and immunohistochemical methods. The plaque necrotic center/fiber cap (NC/FC) ratio and vulnerability index were calculated to evaluate plaque vulnerability. Twenty-four hours after TUS treatment at 3.0 MPa, the MVD in the plaque was substantially decreased by 84% (p < 0.05), while there was almost no change in MVD and neovessel density (NVD) in normal tissues, including skeletal muscle, mesentery and skin. Additionally, a marked reduction in the number of immature vessels was observed in the plaques (reduced by 90%, p < 0.05), whereas the number of mature vessels was not significantly decreased. Furthermore, TUS treatment at 3.0 MPa significantly improved plaque stability, as reflected by the NC/FC ratio and vulnerability index, which may be due to the selective destruction of intraplaque neovascularization by TUS treatment, thereby decreasing the extravasation of erythrocytes and leading to vascular inflammation alleviation and thin-cap fibroatheroma reduction. Conclusions: TUS treatment at 3.0 MPa selectively depleted plaque neovessels and improved the stability of vulnerable plaques through a reduction in erythrocyte extravasation and inflammatory mediator influx, with no significant effect on normal tissue.

Dataset Information

Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility.

Background

Methods and results

Conclusions

Publications

Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility.

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