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 and arterial blood pressure. PGE2, a chief cyclooxygenase product, modulates blood pressure and fertility, although the specific G protein-coupled receptors 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.

EP1‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A2 receptor

“…While EP 1 , FP and TP receptors are each broadly classified as members of the contractile subgroup of prostanoid receptors , functionally they are primarily associated with distinct physiologic processes and each exhibit distinct patterns of expression Sugimoto et al, 2000). Consistent with the latter, mice deficient in each of these receptors display unique characteristic phenotypes including a reduction in carcinogen-induced colorectal cancer in EP 1 -deficient mice (Ushikubi et al, 1998;Watanabe et al, 1999;Sugimoto et al, 2000), loss of parturition affecting both ovulation and fertilization in FPdeficient mice Hizaki et al, 1999;Kennedy et al, 1999) and increased bleeding tendency associated with TP-deficient mice (Thomas et al, 1998). While EP 1 , FP and TP receptors are also abundantly expressed in the kidney (Sugimoto et al, 2000) and they are each reported to mediate efficient contraction of renal vascular SM and mesangial cells through Ca 2 þ -dependent mechanisms (Mene et al, 1989), their role in renal function as garnered from mouse knockout studies remains to be clearly established.…”

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

“…COX-2-knockout mice on CD1d background [38] and EP2 receptor-knockout mice on C57BL/6 background [39] were used for the experiments. Control mice on CD1d and C57BL/6 background were purchased from Charles River Laboratory.…”

Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist

“…For experiments, males and females with deletion of one EP2 receptor allele (Het) were crossed to obtain KO, Het and WT littermates. EP2 receptor KO mice were initially in C57BL/6 X 129 background {the kind gift of Richard M. Breyer, Vanderbilt University Medical Center, Nashville, 1999, [10]} and were backcrossed more than 9 generations into the C57BL/6 background. Genotyping protocols were followed as described previously [11].…”