期刊
SCIENCE ADVANCES
卷 7, 期 12, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf6054
关键词
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资金
- British Heart Foundation [FS/16/1/31699, RG/18/4/33541]
- NIH/National Cancer Institute [R01-CA084572, R01-CA123055, P50-CA086306]
- Phelps Family Foundation
- Crump Family Foundation
The endothelial cyclooxygenase-1 produces both protective and pathological products, ultimately leading to pathological responses such as vasoconstriction in vitro and the development of atherosclerosis and vascular inflammation in vivo. This highlights the potential of the vascular cyclooxygenase-1 pathway as a therapeutic target and emphasizes that the role of prostanoids in biology is complex and context-dependent.
Endothelial cyclooxygenase-1-derived prostanoids, including prostacyclin, have clear cardioprotective roles associated with their anti-thrombotic potential but have also been suggested to have paradoxical pathological activities within arteries. To date it has not been possible to test the importance of this because no models have been available that separate vascular cyclooxygenase-1 products from those generated elsewhere. Here, we have used unique endothelial-specific cyclooxygenase-1 knockout mice to show that endothelial cyclooxygenase-1 produces both protective and pathological products. Functionally, however, the overall effect of these was to drive pathological responses in the context of both vasoconstriction in vitro and the development of atherosclerosis and vascular inflammation in vivo. These data provide the first demonstration of a pathological role for the vascular cyclooxygenase-1 pathway, highlighting its potential as a therapeutic target. They also emphasize that, across biology, the role of prostanoids is not always predictable due to unique balances of context, products, and receptors.
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