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Inhibition of endothelial progenitor cell glycogen synthase kinase-3β results in attenuated neointima formation and enhanced re-endothelialization after arterial injury
- Source :
- Cardiovascular Research. 83:16-23
- Publication Year :
- 2009
- Publisher :
- Oxford University Press (OUP), 2009.
-
Abstract
- Aims Endothelial progenitor cells (EPCs) are circulating pluripotent vascular cells capable of enhancing re-endothelialization and diminishing neointima formation following arterial injury. Glycogen synthase kinase (GSK)-3β is a protein kinase that has been implicated in the regulation of progenitor cell biology. We hypothesized that EPC abundance and function could be enhanced with the use of an inhibitor of GSK-3β (GSKi), thereby resulting in improved arterial repair. Methods and results Human EPCs were expanded e x vivo , treated with a specific GSKi, and then assessed for both yield and functional characteristics by in vitro assays for adherence, apoptosis, and survival. In vivo functionality of treated human EPCs was assessed in immune-tolerant mice subjected to femoral artery wire injury. Re-endothelialization was assessed at 72 h and neointima formation at 7 and 14 days following injury. GSKi treatment resulted in an improvement in the yield of EPCs and a reduction in apoptosis in cells derived from both healthy controls and patients with coronary artery disease. Treatment also increased vascular endothelial growth factor secretion, up-regulated expression of mRNA for the α-4 integrin subunit, and improved adhesion, an effect which could be abrogated with an α-4 integrin blocking antibody. EPCs without or with ex vivo GSKi treatment enhanced re-endothelialization 72 h following injury as well as reduced neointima formation at 7 days (e.g. endothelial coverage: 7.2 ± 1.7% vs. 70.7 ± 5.8% vs. 87.2 ± 4.1%; intima to media ratios: 1.05 ± 0.19 vs. 0.39 ± 0.08 vs. 0.14 ± 0.02; P < 0.05 for all comparisons), an effect that was persistent at 14 days. Conclusion GSKi improves the functional profile of EPCs and is associated with improved re-endothelialization and reduced neointima formation following injury.
- Subjects :
- Vascular Endothelial Growth Factor A
Neointima
Endothelium
Cell Survival
Physiology
Integrin alpha4
Apoptosis
Biology
Endothelial progenitor cell
Andrology
Glycogen Synthase Kinase 3
Mice
chemistry.chemical_compound
Physiology (medical)
Cell Adhesion
medicine
Animals
Homeostasis
Humans
Urea
Enzyme Inhibitors
Progenitor cell
GSK3B
Cells, Cultured
Glycogen Synthase Kinase 3 beta
Neovascularization, Pathologic
Mesenchymal Stem Cells
Arteries
Vascular endothelial growth factor
Endothelial stem cell
Thiazoles
Vascular endothelial growth factor A
medicine.anatomical_structure
chemistry
Models, Animal
Immunology
cardiovascular system
Endothelium, Vascular
Tunica Intima
Cardiology and Cardiovascular Medicine
Subjects
Details
- ISSN :
- 17553245 and 00086363
- Volume :
- 83
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Research
- Accession number :
- edsair.doi.dedup.....32f975b756c4c8913ca1ae3116557bed