Salt–sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP₂ receptor

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, ovulation^1,2 and arterial blood pressure^3,4. PGE₂, a chief cyclooxygenase product, modulates blood pressure and fertility, although the specific G protein–coupled receptors^5,6 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.