Nature Medicine
5, 217 - 220 (1999)
doi:10.1038/5583
Salt−sensitive hypertension and reduced fertility in mice lacking
the prostaglandin EP2 receptorChristopher R.J. Kennedy1, Yahua Zhang1, 5, Suzanne Brandon1, Youfei Guan1, 5, Keith Coffee2, Colin D. Funk2, 6, Mark A. Magnuson4, John A. Oates2, Matthew D. Breyer1, 4, 5
& Richard M. Breyer1, 31
Department of Medicine (Division of Nephrology) Vanderbilt University School of Medicine, S3223 MCN, 1161 21st Avenue South, Nashville, Tennessee 37232−2372, USA
2
Department of Medicine (Division of Clinical Pharmacology) Vanderbilt University School of Medicine, S3223 MCN, 1161 21st Avenue South, Nashville, Tennessee 37232−2372, USA
3
Department of Pharmacology, Vanderbilt University School of Medicine, S3223 MCN, 1161 21st Avenue South, Nashville, Tennessee 37232−2372, USA
4
Department of Molecular Physiology and Biophysics Vanderbilt University School of Medicine, S3223 MCN, 1161 21st Avenue South, Nashville, Tennessee 37232−2372, USA
5
Veterans Administration Medical Center, Vanderbilt University School of Medicine, S3223 MCN, 1161 21st Avenue South, Nashville, Tennessee 37232−2372, USA
6
C.D.F. present address: Department of Pharmacology, University of Pennsylvania, Stellar−Chance Laboratories, Room 805, 422 Curie Boulevard, Philadelphia, Pennsylvania
10104, USA
Correspondence should be addressed to Richard M. Breyer rich.breyer@mcmail.vanderbilt.eduProstaglandins (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 EP
2
−/− 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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