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 [Sar1, Ile5]Ang II, most (> 90%) of which was of the AT2 subtype. In nonpregnant myometrium (n = 5), receptor density [maximum binding capacity (Bmax)] and dissociation constant (Kd) 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), Bmax 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 Bmax (54 +/- 12 fmol/mg protein, n = 4). AT2 Bmax or Kd values in uterine leiomyomas from nonpregnant women showed no significant differences from those in nonpregnant myometrium. Changes of AT2 Bmax in uterine leiomyomas during pregnancy or with oral contraceptive 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.
Matsumoto
T
T
Department of Gynecology and Obstetrics, Kyoto University Faculty of Medicine, Japan.
Sagawa
N
N
Mukoyama
M
M
Tanaka
I
I
Itoh
H
H
Goto
M
M
Itoh
H
H
Horiuchi
M
M
Dzau
V J
VJ
Mori
T
T
Nakao
K
K
D000328:Adult; D000804:Angiotensin II / Q000378:metabolism*; D015152:Blotting, Northern; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000737:chemistry*; D008875:Middle Aged; D009215:Myometrium / Q000737:chemistry*; D011247:Pregnancy / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay; D011945:Receptors, Angiotensin / Q000032:analysis* / Q000235:genetics; D014594:Uterine Neoplasms / Q000737:chemistry*
D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D000804:Angiotensin II