Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Jane A. Mitchell
  • Fisnik Shala
  • Maria Elisa Lopes Pires
  • Rachel Y. Loy
  • Andrew Ravendren
  • Joshua Benson
  • Paula Urquhart
  • Harvey R. Herschman
  • Nicholas S. Kirkby

Abstract

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)eabf6054
JournalScience Advances
Volume7
Issue number12
DOIs
Publication statusPublished - 19 Mar 2021