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 (AT(1)) and type 2 (AT(2)). The AT(2) receptor is abundant in the fet us and decreases rapidly after birth. The uterus expresses the AT, rec eptor abundantly even in adults, suggesting its role in reproduction. To explore the roles and regulation of the AT, receptor in human uteru s and to examine whether its expression is related to the proliferativ e characteristics of leiomyoma, we studied Ang II receptor gene expres sions 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 bind ing for [Sar(1),IIe(8)]Ang II, most (> 90%) of which was of the AT(2) subtype. In nonpregnant myometrium (n = 5), receptor density [maximum binding capacity (B-max)] and dissociation constant (K-d) for AT(2)-se lective 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 AT(2) receptor was significantly decreased (62 +/- 17 and 25 +/- 6 fmol/mg protein, respectively). Furthermore, admin istration of combined oral contraceptive pills induced a comparable re duction in AT(2) B-max (54 +/- 12 fmol/mg protein, n = 4). AT(2) B-max or K-d values in uterine leiomyomas from nonpregnant women showed no significant differences from those in nonpregnant myometrium. Changes of AT(2) B-max in uterine leiomyomas during pregnancy or with oral con traceptives were similar to those in the myometrium. Northern blots re vealed AT(1) and AT(2) receptor messenger RNA (mRNA) expressions in al l samples examined; the former was much lower than the latter. Althoug h the AT(1) receptor mRNA expression did not change significantly, the AT(2) receptor mRNA level was significantly decreased during pregnanc y or with oral contraceptives. These results indicate that AT(1) and A T(2) receptors are expressed in human myometrium and uterine leiomyoma , in which the AT(2) receptor is predominant. AT(2) receptor gene expr ession is down-regulated during pregnancy, possibly mediated by sex st eroids.