Audoly L P, Tilley S L, Goulet J, Key M, Nguyen M, Stock J L, McNeish J D, Koller B H, Coffman T M
Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina 27710, USA.
Am J Physiol. 1999 Sep;277(3):H924-30. doi: 10.1152/ajpheart.1999.277.3.H924.
To identify the E-prostanoid (EP) receptors that mediate the hemodynamic actions of PGE2, we studied acute vascular responses to infusions of PGE2 using lines of mice in which each of four EP receptors (EP1 through EP4) have been disrupted by gene targeting. In mixed groups of males and females, vasodepressor responses after infusions of PGE2 were significantly diminished in the EP2 -/- and EP4 -/- lines but not in the EP1 -/- or EP3 -/- lines. Because the actions of other hormonal systems that regulate blood pressure differ between sexes, we compared the roles of individual EP receptors in males and females. We found that the relative contribution of each EP-receptor subclass was strikingly different in males from that in females. In females, the EP2 and EP4 receptors, which signal by stimulating adenylate cyclase, mediate the major portion of the vasodepressor response to PGE2. In males, the EP2 receptor has a modest effect, but most of the vasodepressor effect is mediated by the phospholipase C-coupled EP1 receptor. Finally, in male mice, the EP3 receptor actively opposes the vasodepressor actions of PGE2. Thus the hemodynamic actions of PGE2 are mediated through complex interactions of several EP-receptor subtypes, and the role of individual EP receptors differs dramatically in males from that in females. These differences may contribute to sexual dimorphism of blood pressure regulation.
为了确定介导前列腺素E2(PGE2)血流动力学作用的前列环素(EP)受体,我们使用通过基因靶向破坏了四种EP受体(EP1至EP4)中每一种的小鼠品系,研究了对输注PGE2的急性血管反应。在雄性和雌性混合组中,输注PGE2后的血管减压反应在EP2 -/- 和EP4 -/- 品系中显著减弱,但在EP1 -/- 或EP3 -/- 品系中未减弱。由于调节血压的其他激素系统的作用在性别之间存在差异,我们比较了单个EP受体在雄性和雌性中的作用。我们发现每个EP受体亚类的相对贡献在雄性和雌性中显著不同。在雌性中,通过刺激腺苷酸环化酶发出信号的EP2和EP4受体介导了对PGE2血管减压反应的主要部分。在雄性中,EP2受体的作用较小,但大部分血管减压作用由与磷脂酶C偶联的EP1受体介导。最后,在雄性小鼠中,EP3受体积极对抗PGE2的血管减压作用。因此,PGE2的血流动力学作用是通过几种EP受体亚型的复杂相互作用介导的,并且单个EP受体的作用在雄性和雌性中差异巨大。这些差异可能导致血压调节的性别二态性。