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

Shakil Ahmad, Peter Hewett, Takeshi Fujisawa, Samir Sissaoui, Meng Cai, Geraldine Gueron, Bahjat Al-Ani, Melissa Cudmore, Syed Faraz Ahmed, M. K. K. Wong, Barbara Wegiel, Leo Otterbein, Libor Vitek, Wenda Ramma, Ke-Qing Wang, Asif Ahmed

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)329-337
Number of pages9
JournalThrombosis and Haemostasis
Issue number2
Early online date30 Oct 2014
Publication statusPublished - Mar 2015


  • Carbon monoxide
  • vascular endothelial growth factor
  • angiogenesis
  • endothelial cells
  • vascular endothelial growth factor receptor-2


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