Abstract
Prostaglandins (PGs) are ubiquitous lipid mediators derived from cyclooxygenase metabolism of arachidonic acid that exert a broad range of physiologic activities, including modulation of inflammation, ovulation1,2 and arterial blood pressure3,4. PGE2, a chief cyclooxygenase product, modulates blood pressure and fertility, although the specific G protein–coupled receptors5,6 mediating these effects remain poorly defined. To evaluate the physiologic role of the PGE2 EP2 receptor subtype, we created mice with targeted disruption of this gene (EP2–/–). EP2–/– mice develop normally but produce small litters and have slightly elevated baseline systolic blood pressure. In EP2–/– mice, the characteristic hypotensive effect of intravenous PGE2 infusion was absent; PGE2 infusion instead produced hypertension. When fed a diet high in salt, the EP2–/– mice developed profound systolic hypertension, whereas wild–type mice showed no change in systolic blood pressure. Analysis of wild–type and EP2–/– mice on day 5 of pregnancy indicated that the reduced litter size of EP2–/– mice is due to a pre–implantation defect. This reduction of implanted embryos could be accounted for by impaired ovulation and dramatic reductions in fertilization observed on day 2 of pregnancy. These data demonstrate that the EP2 receptor mediates arterial dilatation, salt–sensitive hypertension, and also plays an essential part in female fertility.
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Acknowledgements
We thank A. George, T. Inagami and D. Threadgill for critical reading of the manuscript. Gene targeting and embryonic stem cell microinjection were done by the Vanderbilt Transgenic/ES Cell Shared Resource. Support for this project was provided in part by NIH grants GM–15431 (J.A.O. and R.M.B.), DK–46205 (R.M.B.) and DK–37097 (M.D.B.). C.R.J.K. is the recipient of an NKF fellowship.
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Kennedy, C., Zhang, Y., Brandon, S. et al. Salt–sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nat Med 5, 217–220 (1999). https://doi.org/10.1038/5583
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DOI: https://doi.org/10.1038/5583
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