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. 1999 Jun;103(11):1539-45.
doi: 10.1172/JCI6579.

Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor

S L Tilley  1 , L P Audoly, E H Hicks, H S Kim, P J Flannery, T M Coffman, B H Koller
Affiliations

Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor

S L Tilley et al. J Clin Invest. 1999 Jun.

Abstract

Prostaglandins (PGs) are bioactive lipids that modulate a broad spectrum of biologic processes including reproduction and circulatory homeostasis. Although reproductive functions of mammals are influenced by PGs at numerous levels, including ovulation, fertilization, implantation, and decidualization, it is not clear which PGs are involved and whether a single mechanism affects all reproductive functions. Using mice deficient in 1 of 4 prostaglandin E2 (PGE2) receptors -- specifically, the EP2 receptor -- we show that Ep2(-/-) females are infertile secondary to failure of the released ovum to become fertilized in vivo. Ep2(-/-) ova could be fertilized in vitro, suggesting that in addition to previously defined roles, PGs may contribute to the microenvironment in which fertilization takes place. In addition to its effects on reproduction, PGE2 regulates regional blood flow in various vascular beds. However, its role in systemic blood pressure homeostasis is not clear. Mice deficient in the EP2 PGE2 receptor displayed resting systolic blood pressure that was significantly lower than in wild-type controls. Blood pressure increased in these animals when they were placed on a high-salt diet, suggesting that the EP2 receptor may be involved in sodium handling by the kidney. These studies demonstrate that PGE2, acting through the EP2 receptor, exerts potent regulatory effects on two major physiologic processes: blood pressure homeostasis and in vivo fertilization of the ovum.

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Figures

Figure 1
Figure 1
Disruption of the gene encoding the EP2 receptor. (a) Restriction maps of the targeting construct, endogenous locus, and targeted locus. The dark filled box represents exon sequences of the Ep2 gene. The open boxes represent phosphoglycerate kinase-thymidine kinase (PGK-TK) and PGK-Neo selection cassettes. Homologous recombination of the targeting vector with the endogenous locus results in deletion of a 355-bp segment of DNA that is predicted to encode 3 transmembrane domains and 2 intracellular loops of mature EP2 protein. The hatch filled box represents the probe used to detect homologous recombination events by Southern blot analysis. Relevant restriction sites are abbreviated by the following: B, BamHI; E, EagI; H, HindIII; L, BglI; N, NsiI; Nt, NotI; R, EcoRI; S, SacII. Note that not all HindIII sites are mapped. (b) Southern blot analysis of DNA obtained from tail biopsies of offspring from Ep2+/– heterozygote breedings. HindIII-digested DNA was analyzed using a 1.1-kb EcoRI probe corresponding to DNA outside the targeted region of the Ep2 gene. This probe detects a 7-kb band derived from the endogenous locus and an 8.5-kb band from the targeted locus. (c) RT-PCR amplification of Ep2 total RNA from uteri of Ep2–/– and Ep2+/+ mice. Ep2-specific cDNA was synthesized by RT-PCR. The left lanes represent cDNA from 2 Ep2–/– animals; the lane on the far right represents cDNA from an Ep2+/+ animal. To ensure that the failure to detect an Ep2-specific DNA fragment in the mRNA obtained from Ep2–/– animals was not due to the absence of RNA, the same samples were subjected to RT-PCR using actin-specific primers.
Figure 2
Figure 2
Ovulation and fertilization in Ep2–/– and Ep2+/+ mice. Female Ep2–/– (n = 8) and Ep2+/+ (n = 5) mice were mated with wild-type males, and ovulation and in vivo fertilization were determined by counting eggs and embryos 2 days following coitus. For in vitro fertilization, eggs from mice of both genotypes were collected 12 hours after ovulation and cultured with sperm obtained from wild-type males. Fertilization was scored by counting the number of 2-cell embryos 24 hours later. *P < 0.0001.
Figure 3
Figure 3
PRA in Ep2–/– and Ep2+/+ mice on normal and high-salt diets. Plasma was prepared from Ep2–/– (n = 8) and Ep2+/+(n = 7) mice on a normal diet (0.4% NaCl), and PRA was determined by radioimmunoassay. PRA was also measured in Ep2–/– (n = 5) and Ep2+/+(n = 6) mice after 10 days on a high-salt diet (6% NaCl). Data represent mean ± SEM.
Figure 4
Figure 4
Renin mRNA levels in Ep2–/– and Ep2+/+ mice. RNA was obtained from the kidneys of Ep2–/– (n = 8) and Ep2+/+(n = 7) mice on a normal diet (0.4% NaCl), and renin mRNA levels were determined by RNase protection assay. Data represent mean ± SEM.
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