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CD40 ligand+ microparticles from human atherosclerotic plaques stimulate endothelial proliferation and angiogenesis a potential mechanism for intraplaque neovascularization.
- Source :
-
Journal of the American College of Cardiology [J Am Coll Cardiol] 2008 Oct 14; Vol. 52 (16), pp. 1302-11. - Publication Year :
- 2008
-
Abstract
- Objectives: Our goal was to demonstrate that microparticles (MPs) are the endogenous signal leading to neovessel formation through CD40 ligation in human atherosclerotic plaques.<br />Background: Vulnerable atherosclerotic plaques prone to rupture are characterized by an increased number of vasa vasorum and frequent intraplaque hemorrhage. Although inflammatory cytokines, growth factors, or CD40/CD40 ligand (CD40L) are possible candidates, the mechanism of atherosclerotic plaque neovascularization remains unknown. Atherosclerotic plaques contain large amounts of membrane-shed submicron MPs released after cell activation or apoptosis.<br />Methods: Microparticles were isolated from endarterectomy specimens surgically obtained from 26 patients and characterized by phosphatidylserine exposure and specific markers of cellular origin.<br />Results: Plaque MPs increased both endothelial proliferation assessed by (3)H-thymidine incorporation and cell number and stimulated in vivo angiogenesis in Matrigel (BD Biosciences, San Diego, California) assays performed in wild-type and BalbC/Nude mice, whereas circulating MPs had no effect. Microparticles from symptomatic patients expressed more CD40L and were more potent in inducing endothelial proliferation, when compared with asymptomatic plaque MPs. Most of CD40L+ MPs (93%) isolated from human plaques were of macrophage origin. Microparticle-induced endothelial proliferation was impaired by CD40L or CD40-neutralizing antibodies and abolished after endothelial CD40-ribonucleic acid silencing. In addition, the proangiogenic effect of plaque MPs was abolished in Matrigel assays performed in the presence of CD40L-neutralizing antibodies or in CD40-deficient mice.<br />Conclusions: These results demonstrate that MPs isolated from human atherosclerotic lesions express CD40L, stimulate endothelial cell proliferation after CD40 ligation, and promote in vivo angiogenesis. Therefore, MPs could represent a major determinant of intraplaque neovascularization and plaque vulnerability.
- Subjects :
- Aged
Apoptosis physiology
Atherosclerosis pathology
Carotid Artery Diseases pathology
Carotid Artery Diseases surgery
Cell Proliferation
Cells, Cultured
Culture Media
Endarterectomy methods
Endothelium, Vascular pathology
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Humans
Male
Neovascularization, Pathologic pathology
Particle Size
Reference Values
Sensitivity and Specificity
Atherosclerosis metabolism
CD40 Ligand metabolism
Carotid Artery Diseases metabolism
Endothelium, Vascular metabolism
Neovascularization, Pathologic metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-3597
- Volume :
- 52
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of the American College of Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 18929241
- Full Text :
- https://doi.org/10.1016/j.jacc.2008.07.032