Effects of estrogen on the vascular injury response in estrogen receptor α,β (double) knockout mice
Effects of estrogen on the vascular injury response in estrogen receptor α,β (double) knockout mice
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DOI：
10.1161/hh1801.097239
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发表时间：
2001-09-14
影响因子：
20.1
通讯作者：
Mendelsohn, ME
中科院分区：
文献类型：
--
作者：
Karas, RH;Schulten, H;Mendelsohn, ME
两种已知的雌激素受体，ER α和ER β，介导雌激素在所有靶组织中的作用，包括血管。我们先前已经表明雌激素在雌性野生型（WT）、ER α敲除（ER α KOCH）和ER β敲除（ER β KOCH）小鼠中抑制血管损伤反应的程度相同。我们通过繁殖产生了携带ER α和ER β基因（ER α，β KOCH）破坏的小鼠，并研究了17 β-雌二醇（E2）对卵巢切除雌性ER α，β KOCH小鼠和WT同窝出生小鼠血管损伤反应的影响。E2抑制WT小鼠损伤后血管中膜面积的增加，但不抑制ER α、β KOCH小鼠损伤后血管中膜面积的增加，这首次证明两种已知的雌激素受体对于介导血管损伤反应组分的雌激素抑制是必要且充分的。令人惊讶的是，在WT同窝出生的小鼠中，E2仍然显著增加ER α，β KOCH小鼠损伤后的子宫重量并抑制血管平滑肌细胞（VSMC）增殖。这些数据支持雌激素受体在ER α，β KOCH小鼠血管损伤反应的特定组分中的作用不同。结果未解决E2抑制ER α，β KOCH小鼠VSMC增殖是否是由受体非依赖性机制引起的，一种未鉴定的对雌激素有反应的受体，或先前在亲代ER α KOCH小鼠中报道的ER α剪接变体的残留活性。这些可能性可以通过对ER α完全破坏的小鼠（ER α KOSt）的研究来解决，这些研究正在进行中。
The two known estrogen receptors, ER alpha and ER beta, mediate the effects of estrogen in all target tissues, including blood vessels. We have shown previously that estrogen inhibits vascular injury response to the same extent in female wild-type (WT), ERa knockout (ER alpha KOCH), and ER beta knockout (ER beta KOCH) mice. We generated mice harboring disruptions of both ER alpha and ER beta genes (ER alpha,beta KOCH) by breeding and studied the effect of 17 beta -estradiol (E2) on vascular injury responses in ovariectomized female ER alpha,beta KOCH mice and WT littermates. E2 inhibited increases in vascular medial area following injury in the WT mice but not in the ER alpha,beta KOCH mice, demonstrating for the first time that the two known estrogen receptors are necessary and sufficient to mediate estrogen inhibition of a component of the vascular injury response. Surprisingly, as in WT littermates, E2 still significantly increased uterine weight and inhibited vascular smooth muscle cell (VSMC) proliferation following injury in the ER alpha,beta KOCH mice. These data support that the role of estrogen receptors differs for specific components of the vascular injury response in the ER alpha,beta KOCH mice. The results leave unresolved whether E2 inhibition of VSMC proliferation in ER alpha,beta KOCH mice is caused by a receptor-independent mechanism, an unidentified receptor responsive to estrogen, or residual activity of the ER alpha splice variant reported previously in the parental ER alpha KOCH mice. These possibilities may be resolved by studies of mice in which ER alpha has been fully disrupted (ER alpha KOSt), which are in progress.