Liu Hong-Wei, Iwai Masaru, Takeda-Matsubara Yuko, Wu Lan, Li Jian-Mei, Okumura Midori, Cui Tai-Xing, Horiuchi Masatsugu
Department of Medical Biochemistry, Ehime University School of Medicine, Ehime, Japan.
Hypertension. 2002 Oct;40(4):451-7; discussion 448-50. doi: 10.1161/01.hyp.0000033466.05496.89.
The present study explored the possibility that estrogen may enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker on neointima formation in vascular injury, and investigated the signaling mechanism involved in their actions. Polyethylene cuff placement around the femoral artery of mice induced neointima formation and increased bromodeoxyuridine (BrdU) incorporation into vascular smooth muscle cells. These changes were significantly smaller in female mice than in male mice. Ovariectomy enhanced neointima formation and BrdU incorporation in the injured artery, which were reversed by 17beta-estradiol (80 microg/kg per day) replacement. Treatment with a selective AT1 receptor blocker, olmesartan (3 mg/kg per day), significantly inhibited neointima formation and BrdU incorporation, whereas the inhibitory effects of olmesartan were more marked in intact female mice than in male or ovariectomized mice. Phosphorylation of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription (STAT) 1, and STAT3 was increased in the injured artery. These increases were significantly smaller in intact female mice than in male or ovariectomized mice. Olmesartan or estrogen attenuated the phosphorylation of ERK and STAT in the injured artery, whereas these inhibitory effects were greater in intact female mice. Lower doses of olmesartan (0.5 mg/kg per day) or 17beta-estradiol (20 microg/kg per day) did not influence neointima formation, BrdU incorporation, and ERK and STAT phosphorylation in ovariectomized mice, whereas coadministration of olmesartan and 17beta-estradiol at these doses attenuated these parameters. These results indicate that estrogen and an AT1 receptor blocker synergistically attenuate vascular remodeling, which is at least partly via inhibition of ERK and STAT activity.
本研究探讨了雌激素可能增强血管紧张素（Ang）II 1型（AT1）受体阻滞剂对血管损伤后内膜增生的抑制作用，并研究了其作用涉及的信号转导机制。在小鼠股动脉周围放置聚乙烯套管可诱导内膜增生，并增加溴脱氧尿苷（BrdU）掺入血管平滑肌细胞。这些变化在雌性小鼠中明显小于雄性小鼠。卵巢切除增强了损伤动脉中的内膜增生和BrdU掺入，而17β-雌二醇（每天80μg/kg）替代可逆转这些变化。用选择性AT1受体阻滞剂奥美沙坦（每天3mg/kg）治疗可显著抑制内膜增生和BrdU掺入，而奥美沙坦的抑制作用在完整雌性小鼠中比在雄性或去卵巢小鼠中更明显。损伤动脉中细胞外信号调节激酶（ERK）、信号转导和转录激活因子（STAT）1及STAT3的磷酸化增加。这些增加在完整雌性小鼠中明显小于雄性或去卵巢小鼠。奥美沙坦或雌激素可减轻损伤动脉中ERK和STAT的磷酸化，而这些抑制作用在完整雌性小鼠中更强。较低剂量的奥美沙坦（每天0.5mg/kg）或17β-雌二醇（每天20μg/kg）对去卵巢小鼠的内膜增生、BrdU掺入以及ERK和STAT磷酸化没有影响，而这些剂量的奥美沙坦和17β-雌二醇联合给药可减轻这些参数。这些结果表明，雌激素和AT1受体阻滞剂协同减轻血管重塑，这至少部分是通过抑制ERK和STAT活性实现的。
