Carbon monoxide inhibits sprouting angiogenesis and vascular endothelial growth factor receptor-2 phosphorylation

• Published in: Thrombosis and haemostasis Vol. 113; no. 2; p. 329
• Main Authors: Ahmad, Shakil, Hewett, Peter W, Fujisawa, Takeshi, Sissaoui, Samir, Cai, Meng, Gueron, Geraldine, Al-Ani, Bahjat, Cudmore, Melissa, Ahmed, S Faraz, Wong, Michael K K, Wegiel, Barbara, Otterbein, Leo E, Vítek, Libor, Ramma, Wenda, Wang, Keqing, Ahmed, Asif
• Format: Journal Article
• Language: English
• Published: Germany 01.02.2015
• Subjects: Animals; Carbon Monoxide - chemistry; Cell Movement; Cell Proliferation; Collagen - chemistry; Drug Combinations; Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells; Humans; Immunoprecipitation; Laminin - chemistry; Mice, Inbred C57BL; Neovascularization, Pathologic; Organometallic Compounds - chemistry; Phosphorylation; Proteoglycans - chemistry; Recombinant Proteins - chemistry; Tyrosine - chemistry; Vascular Endothelial Growth Factor Receptor-2 - metabolism; endothelial cells; Carbon monoxide; vascular endothelial growth factor receptor-2; angiogenesis; vascular endothelial growth factor
• ISSN: 2567-689X
• DOI: 10.1160/TH14-01-0002

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.