Type 2 angiotensin II receptor is expressed in human myometrium and uterine leiomyoma and is down-regulated during pregnancy

Angiotensin II (Ang II) acts on at least two receptor subtypes, type 1 (AT₁) and type 2 (AT₂). The AT₂ receptor is abundant in the fetus and decreases rapidly after birth. The uterus expresses the AT₂ receptor abundantly even in adults, suggesting its role in reproduction. To explore the roles and regulation of the AT₂ receptor in human uterus and to examine whether its expression is related to the proliferative characteristics of leiomyoma, we studied Ang II receptor gene expressions in nonpregnant and pregnant myometrium and in uterine leiomyomas obtained from patients who underwent gynecological surgery. Receptor binding studies revealed that all samples exhibited high-affinity binding for [Ser¹,Ile⁸]Ang II, most (>90%) of which was of the AT₂ subtype. In nonpregnant myometrium (n = 5), receptor density [maximum binding capacity (B(max))] and dissociation constant (K(d)) for AT₂-selective CGP42112A were 287 ± 46 fmol/mg protein and 0.48 ± 0.09 nM, respectively. In the myometrium of early (n = 6) and late pregnancy (n = 3), B(max) for the AT₂ receptor was significantly decreased (62 ± 17 and 25 ± 6 fmol/mg protein, respectively). Furthermore, administration of combined oral contraceptive pills induced a comparable reduction in AT₂ B(max) (54 ± 12 fmol/mg protein, n = 4). AT₂ B(max) or K(d) values in uterine leiomyomas from nonpregnant women showed no significant differences from those in nonpregnant myometrium. Changes of AT₂ B(max) in uterine leiomyomas during pregnancy or with oral contraceptives were similar to those in the myometrium. Northern blots revealed AT₁ and AT₂ receptor messenger RNA (mRNA) expressions in all samples examined; the former was much lower than the latter. Although the AT₁ receptor mRNA expression did not change significantly, the AT₂ receptor mRNA level was significantly decreased during pregnancy or with oral contraceptives. These results indicate that AT₁ and AT₂ receptors are expressed in human myometrium and uterine leiomyoma, in which the AT₂ receptor is predominant, AT₂ receptor gene expression is down-regulated during pregnancy, possibly mediated by sex steroids.