Smooth muscle cells-derived CXCL10 prevents endothelial healing through PI3Kγ-dependent T cells response.
Cardiovasc Res
; 116(2): 438-449, 2020 02 01.
Article
em En
| MEDLINE
| ID: mdl-31106375
ABSTRACT
AIMS:
Defects in efficient endothelial healing have been associated with complication of atherosclerosis such as post-angioplasty neoatherosclerosis and plaque erosion leading to thrombus formation. However, current preventive strategies do not consider re-endothelialization in their design. Here, we investigate mechanisms linking immune processes and defect in re-endothelialization. We especially evaluate if targeting phosphoinositide 3-kinase γ immune processes could restore endothelial healing and identify immune mediators responsible for these defects. METHODS ANDRESULTS:
Using in vivo model of endovascular injury, we showed that both ubiquitous genetic inactivation of PI3Kγ and hematopoietic cell-specific PI3Kγ deletion improved re-endothelialization and that CD4+ T-cell population drives this effect. Accordingly, absence of PI3Kγ activity correlates with a decrease in local IFNγ secretion and its downstream interferon-inducible chemokine CXCL10. CXCL10 neutralization promoted re-endothelialization in vivo as the same level than those observed in absence of PI3Kγ suggesting a role of CXCL10 in re-endothelialization defect. Using a new established ex vivo model of carotid re-endothelialization, we showed that blocking CXCL10 restore the IFNγ-induced inhibition of endothelial healing and identify smooth muscle cells as the source of CXCL10 secretion in response to Th1 cytokine.CONCLUSION:
Altogether, these findings expose an unforeseen cellular cross-talk within the arterial wall whereby a PI3Kγ-dependent T-cell response leads to CXCL10 production by smooth muscle cells which in turn inhibits endothelial healing. Therefore, both PI3Kγ and the IFNγ/CXCL10 axis provide novel strategies to promote endothelial healing.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Cicatrização
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Linfócitos T CD4-Positivos
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Lesões das Artérias Carótidas
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Miócitos de Músculo Liso
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Células Endoteliais
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Quimiocina CXCL10
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Classe Ib de Fosfatidilinositol 3-Quinase
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Músculo Liso Vascular
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article