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

SHAKIL AHMAD; PETER W. HEWETT; TAKESHI FUJISAWA; SAMIR SISSAOUI; MENG CAI; GERALDINE GUERON; MELISSA CUDMORE; FARAZ AHMED; MICHAEL K. K. WONG; BARBARA WEGIEL; LEO E. OTTERBEIN; LIBOR VÍTEK; WENDA RAMMA; KEQING WANG; ASIF AHMED

JOURNAL OF THROMBOSIS AND HAEMOSTASIS

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2014

1538-7933

Carbon monoxide (CO) is a gaseous autacoid responsible for regulat- ing inflammation, neural transmission and vascular tone. However, the role of CO in angiogenesis is unknown. The aim of this study was to in- vestigate the effect of CO on angiogenesis and vascular endothelial growth factor (VEGF) receptor-2 phosphorylation. In vitro angiogen- esis studies were performed using human umbilical vein endothelial cells (HUVECs) on growth factor-reduced Matrigel 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 reor- ganisation, cell proliferation, migration and capillary-like tube formation. Similarly, CO suppressed VEGF-stimulated VEGFR-2 phos- phorylation at key tyrosine residues and basic fibroblast growth factor (FGF-2) and VEGF mediated Akt phosphorylation in endothelial cells. Consistent with these data, mice exposed to CO gas (250 ppm, 1 hour/ day for 14 days) exhibited a marked decrease in FGF-2-induced Matrigel plug angiogenesis (p< 0.05). These data establish a new bio- logical function for CO in angiogenesis and point to a potential thera- peutic use for CO as an anti-angiogenic agent.