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

Prostaglandins (PGs) are ubiquitous lipid mediators derived from cyclooxyge nase metabolism of arachidonic acid that exert a broad range of physiologic activities, including modulation of inflammation, ovulation(1,2) and arter ial blood pressure(3,4). PGE(2), a chief cyclooxygenase product, modulates blood pressure and fertility, although the specific G protein-coupled recep tors(5,6) mediating these effects remain poorly defined. To evaluate the ph ysiologic role of the PGE(2) EP2 receptor subtype, we created mice with tar geted disruption of this gene (EP2-/-). EP2-/- mice develop normally but pr oduce small litters and have slightly elevated baseline systolic blood pres sure. In EP2-/- mice, the characteristic hypotensive effect of intravenous PGE(2) infusion was absent; PGE(2) infusion instead produced hypertension. When fed a diet high in salt, the EP2-/- mice developed profound systolic h ypertension, whereas wild-type mice showed no change in systolic blood pres sure. 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 d efect. This reduction of implanted embryos could be accounted for by impair ed ovulation and dramatic reductions in fertilization observed on day 2 of pregnancy. These data demonstrate that the EP2 receptor mediates arterial d ilatation, salt-sensitive hypertension, and also plays an essential part in female fertility.