title: Carbon monoxide inhibits sprouting angiogenesis and vascular endothelial growth factor receptor-2 phosphorylation.
abstract: 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.
authors.affiliation: Dr. Shakil Ahmad, Aston Medical School, Aston University, Birmingham B4 7ET, UK, Tel.: +44 121 204 4038, E-mail: s.ahmad@aston.ac.uk.
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hewett
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Samir
authors.initials: S
authors.lastname: Sissaoui
authors.forename: Meng
authors.initials: M
authors.lastname: Cai
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gueron
authors.forename: Bahjat
authors.initials: B
authors.lastname: Al-Ani
authors.forename: Melissa
authors.initials: M
authors.lastname: Cudmore
authors.forename: S Faraz
authors.initials: SF
authors.lastname: Ahmed
authors.forename: Michael K K
authors.initials: MK
authors.lastname: Wong
authors.forename: Barbara
authors.initials: B
authors.lastname: Wegiel
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Libor
authors.initials: L
authors.lastname: Vítek
authors.forename: Wenda
authors.initials: W
authors.lastname: Ramma
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000737:chemistry*; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047468:Immunoprecipitation; D007797:Laminin / Q000737:chemistry; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D009942:Organometallic Compounds / Q000737:chemistry; D010766:Phosphorylation; D011509:Proteoglycans / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D009942:Organometallic Compounds; D011509:Proteoglycans; D011994:Recombinant Proteins; C447082:tricarbonyldichlororuthenium (II) dimer; C059485:matrigel; D014443:Tyrosine; D002248:Carbon Monoxide; D003094:Collagen; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Carbon monoxide; angiogenesis; endothelial cells; vascular endothelial growth factor; vascular endothelial growth factor receptor-2