Back to Search
Start Over
Smooth muscle cells-derived CXCL10 prevents endothelial healing through PI3Kγ-dependent T cells response.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2020 Feb 01; Vol. 116 (2), pp. 438-449. - Publication Year :
- 2020
-
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.<br />Methods and Results: 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.<br />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.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
CD4-Positive T-Lymphocytes immunology
Carotid Artery Injuries genetics
Carotid Artery Injuries immunology
Carotid Artery Injuries pathology
Cell Proliferation
Cells, Cultured
Class Ib Phosphatidylinositol 3-Kinase deficiency
Class Ib Phosphatidylinositol 3-Kinase genetics
Disease Models, Animal
Endothelial Cells pathology
Human Umbilical Vein Endothelial Cells metabolism
Humans
Interferon-gamma metabolism
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular immunology
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle immunology
Myocytes, Smooth Muscle pathology
Paracrine Communication
Re-Epithelialization
Signal Transduction
CD4-Positive T-Lymphocytes enzymology
Carotid Artery Injuries enzymology
Chemokine CXCL10 metabolism
Class Ib Phosphatidylinositol 3-Kinase metabolism
Endothelial Cells metabolism
Muscle, Smooth, Vascular metabolism
Myocytes, Smooth Muscle metabolism
Wound Healing
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 116
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 31106375
- Full Text :
- https://doi.org/10.1093/cvr/cvz122