Identification of specific EP receptors responsible for the hemodynamic effects of PGE2

To identify the E-prostanoid (EP) receptors that mediate the hemodynamic actions of PGE(2), we studied acute vascular responses to infusions of PGE(2) 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 PGE(2) 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 PGE(2). Thus the hemodynamic actions of PGE(2) 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.