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
Dr. Shakil Ahmad, Aston Medical School, Aston University, Birmingham B4 7ET, UK, Tel.: +44 121 204 4038, E-mail:
Thromb Haemost. 2015 Feb;113(2):329-37. doi: 10.1160/TH14-01-0002. Epub 2014 Oct 30.
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.
一氧化碳（CO）是一种气态自分泌调节物质，已知其可正向调节血管张力；然而，其在血管生成中的作用尚不清楚。本研究的目的是探讨CO对血管生成及血管内皮生长因子（VEGF）受体-2磷酸化的影响。人脐静脉内皮细胞（HUVECs）在生长因子减少的基质胶上培养，并用一氧化碳释放分子（CORM-2）处理或暴露于CO气体（250 ppm）中。在此，我们报告了一个惊人的发现，即暴露于CO会抑制血管内皮生长因子（VEGF）诱导的内皮细胞肌动蛋白重组、细胞增殖、迁移和毛细血管样管形成。同样，CO抑制VEGF介导的VEGFR-2在酪氨酸残基1175和1214处的磷酸化以及碱性成纤维细胞生长因子（FGF-2）和VEGF介导的Akt磷酸化。与这些数据一致，暴露于250 ppm CO（每天1小时，共14天）的小鼠在FGF-2诱导的基质胶栓血管生成中表现出显著下降（p<0.05）。这些数据确立了CO在血管生成中的一种新生物学功能，并指出CO作为一种抗血管生成剂在肿瘤抑制中的潜在治疗用途。
