- MeSH
- adventicie MeSH
- aterosklerotický plát * genetika MeSH
- ateroskleróza * genetika MeSH
- leukocyty MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- komentáře MeSH
- práce podpořená grantem MeSH
Our objective was to investigate the effect of cholesterol [hypercholesterolemia and 7-ketocholesterol (7K)] on endoglin (Eng) expression and regulation with respect to endothelial or vascular dysfunction in vivo and in vitro. In vivo experiments were performed in 2-mo-old atherosclerosis-prone apolipoprotein E-deficient/LDL receptor-deficient (ApoE-/-/LDLR-/-) female mice and their wild-type C57BL/6J littermates. In in vitro experiments, human aortic endothelial cells (HAECs) were treated with 7K. ApoE-/-/LDLR-/- mice developed hypercholesterolemia accompanied by increased circulating levels of P-selectin and Eng and a disruption of NO metabolism. Functional analysis of the aorta demonstrated impaired vascular reactivity, and Western blot analysis revealed down-regulation of membrane Eng/Smad2/3/eNOS signaling in ApoE-/-/LDLR-/- mice. 7K increased Eng expression via Krüppel-like factor 6 (KLF6), liver X nuclear receptor, and NF-κB in HAECs. 7K-induced Eng expression was prevented by the treatment with 2-hydroxypropyl-β-cyclodextrin; 8-{[5-chloro-2-(4-methylpiperazin-1-yl) pyridine-4-carbonyl] amino}-1-(4-fluorophenyl)-4, 5-dihydrobenzo[g]indazole-3-carboxamide; or by KLF6 silencing. 7K induced increased adhesion and transmigration of monocytic human leukemia promonocytic cell line cells and was prevented by Eng silencing. We concluded that hypercholesterolemia altered Eng expression and signaling, followed by endothelial or vascular dysfunction before formation of atherosclerotic lesions in ApoE-/-/LDLR-/- mice. By contrast, 7K increased Eng expression and induced inflammation in HAECs, which was followed by an increased adhesion and transmigration of monocytes via endothelium, which was prevented by Eng inhibition. Thus, we propose a relevant role for Eng in endothelial or vascular dysfunction or inflammation when exposed to cholesterol.-Vicen, M., Vitverova, B., Havelek, R., Blazickova, K., Machacek, M., Rathouska, J., Najmanová, I., Dolezelova, E., Prasnicka, A., Sternak, M., Bernabeu, C., Nachtigal, P. Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro.
- Klíčová slova
- endothelial cells, hypercholesterolemia, mice, oxysterols,
- MeSH
- aorta cytologie metabolismus patologie MeSH
- apolipoproteiny E genetika MeSH
- aterosklerotický plát etiologie genetika metabolismus MeSH
- beta-cyklodextriny farmakologie MeSH
- cévní endotel účinky léků metabolismus patologie MeSH
- cholesterol metabolismus MeSH
- endoglin genetika metabolismus MeSH
- hypercholesterolemie komplikace genetika metabolismus MeSH
- indazoly farmakologie MeSH
- KLF6 metabolismus MeSH
- kultivované buňky MeSH
- kyseliny isonikotinové farmakologie MeSH
- LDL-receptory genetika MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- NF-kappa B metabolismus MeSH
- oxid dusnatý metabolismus MeSH
- P-selektin metabolismus MeSH
- proteiny Smad metabolismus MeSH
- synthasa oxidu dusnatého, typ III metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- apolipoproteiny E MeSH
- beta-cyklodextriny MeSH
- cholesterol MeSH
- endoglin MeSH
- indazoly MeSH
- Klf6 protein, mouse MeSH Prohlížeč
- KLF6 MeSH
- kyseliny isonikotinové MeSH
- LDL-receptory MeSH
- NF-kappa B MeSH
- oxid dusnatý MeSH
- P-selektin MeSH
- PHA 408 MeSH Prohlížeč
- proteiny Smad MeSH
- synthasa oxidu dusnatého, typ III MeSH
The cellular and molecular basis of vascular calcification (VC) in atherosclerosis is not fully understood. Here, we investigate role of resident/circulating progenitor cells in VC and contribution of inflammatory plaque environment to this process. Vessel-derived stem/progenitor cells (VSCs) and mesenchymal stem cells (MSCs) isolated from atherosclerotic ApoE(-/-) mice showed significantly more in vitro osteogenesis and chondrogenesis than cells generated from control C57BL/6 mice. To assess their ability to form bone in vivo, cells were primed chondrogenically or cultured in control medium on collagen glycosaminoglycan scaffolds in vitro prior to subcutaneous implantation in ApoE(-/-) and C57BL/6 mice using a crossover study design. Atherosclerotic ApoE(-/-) MSCs and VSCs formed bone when implanted in C57BL/6 mice. In ApoE(-/-) mice, these cells generated more mature bone than C57BL/6 cells. The atherosclerotic in vivo environment alone promoted bone formation by implanted C57BL/6 cells. Un-primed C57BL/6 VSCs were unable to form bone in either mouse strain. Treatment of ApoE(-/-) VSC chondrogenic cultures with interleukin (IL)-6 resulted in significantly increased glycosaminoglycan deposition and expression of characteristic chondrogenic genes at 21 days. In conclusion, resident vascular cells from atherosclerotic environment respond to the inflammatory milieu and undergo calcification. IL-6 may have a role in aberrant differentiation of VSCs contributing to vascular calcification in atherosclerosis.
- Klíčová slova
- Atherosclerosis, Chondrogenesis, Collagen scaffold, Endochondral ossification, In vivo, Mesenchymal stem cells, Pericytes, Vascular calcification, Vascular progenitor cells,
- MeSH
- apolipoproteiny E genetika MeSH
- aterosklerotický plát genetika patologie terapie MeSH
- ateroskleróza genetika patologie terapie MeSH
- buněčná diferenciace genetika MeSH
- cévy cytologie MeSH
- chondrogeneze genetika MeSH
- cytokiny metabolismus MeSH
- glykosaminoglykany metabolismus MeSH
- interleukin-6 metabolismus MeSH
- lidé MeSH
- mezenchymální kmenové buňky * MeSH
- myši MeSH
- osteogeneze genetika MeSH
- vaskulární kalcifikace genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- apolipoproteiny E MeSH
- cytokiny MeSH
- glykosaminoglykany MeSH
- interleukin-6 MeSH
