Kennedy C R, Zhang Y, Brandon S, Guan Y, Coffee K, Funk C D, Magnuson M A, Oates J A, Breyer M D, Breyer R M
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372, USA.
Nat Med. 1999 Feb;5(2):217-20. doi: 10.1038/5583.
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.
前列腺素（PGs）是由花生四烯酸经环氧合酶代谢产生的普遍存在的脂质介质，具有广泛的生理活性，包括调节炎症、排卵和动脉血压。PGE2是主要的环氧合酶产物，可调节血压和生育能力，尽管介导这些作用的特定G蛋白偶联受体仍不清楚。为了评估PGE2 EP2受体亚型的生理作用，我们构建了该基因靶向缺失的小鼠（EP2-/-）。EP2-/-小鼠发育正常，但产仔数少，基线收缩压略有升高。在EP2-/-小鼠中，静脉注射PGE2的特征性降压作用消失；相反，注射PGE2会导致高血压。当喂食高盐饮食时，EP2-/-小鼠出现严重的收缩期高血压，而野生型小鼠的收缩压没有变化。对怀孕第5天的野生型和EP2-/-小鼠进行分析表明，EP2-/-小鼠产仔数减少是由于植入前缺陷。植入胚胎数量的减少可以通过怀孕第2天观察到的排卵受损和受精显著减少来解释。这些数据表明，EP2受体介导动脉扩张、盐敏感性高血压，并且在雌性生育中也起着重要作用。
