Journal
THROMBOSIS AND HAEMOSTASIS
Volume 113, Issue 2, Pages 329-337Publisher
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
DOI: 10.1160/TH14-01-0002
Keywords
Carbon monoxide; vascular endothelial growth factor; angiogenesis; endothelial cells; vascular endothelial growth factor receptor-2
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Funding
- British Heart Foundation [RG/09/001/25940]
- Medical Research Council [G0700288]
- Czech Ministry of Education [LH11030]
- MRC [MR/K024868/1, G0600270, G0700288] Funding Source: UKRI
- British Heart Foundation [RG/09/001/25940] Funding Source: researchfish
- Medical Research Council [G0700288, MR/K024868/1, G0600270] Funding Source: researchfish
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Carbon monoxide (CO) is a gaseous autacoid known to positively regulate vascular tone; however, its role in angiogenesis is unknown. The aim of this study was to investigate the effect of CO on angiogenesis and vascular endothelial growth factor (VEGF) receptor-2 phosphorylation. Human umbilical vein endothelial cells (HUVECs) were cultured on growth factor-reduced Matrigel and treated with a CO-releasing molecule (CORM-2) or exposed to CO gas (250 ppm). Here, we report the surprising finding that exposure to CO inhibits vascular endothelial growth factor (VEGF)-induced endothelial cell actin reorganisation, cell proliferation, migration and capillary-like tube formation. Similarly, CO suppressed VEGF-mediated phosphorylation of VEGFR-2 at tyrosine residue 1175 and 1214 and basic fibroblast growth factor- (FGF-2) and VEGF-mediated Akt phosphorylation. Consistent with these data, mice exposed to 250 ppm CO (1h/day for 14 days) exhibited a marked decrease in FGF-2-induced Matrigel plug angiogenesis (p<0.05). These data establish a new biological function for CO in angiogenesis and point to a potential therapeutic use for CO as an anti-angiogenic agent in tumour suppression.
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