Endogenous estrogen deficiency reduces proliferation and enhances apoptosis-related death in vascular smooth muscle cells - Insights from the aromatase-knockout mouse
Endogenous estrogen deficiency reduces proliferation and enhances apoptosis-related death in vascular smooth muscle cells - Insights from the aromatase-knockout mouse
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DOI：
10.1161/01.cir.0000109699.45186.30
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发表时间：
2004-02-03
期刊：
影响因子：
37.8
通讯作者：
Sudhir, K
中科院分区：
文献类型：
--
作者：
Ling, SH;Dai, AZ;Sudhir, K
背景-血管平滑肌细胞（VSMCs）增殖和死亡的改变是血管生长和重塑的重要机制。本研究探讨内源性雌激素对VSMC增殖的影响。方法和结果-使用雌激素缺乏动物模型，芳香酶敲除（ArKO）小鼠。从11周龄雄性、雌性ArKO小鼠和野生型（WT）小鼠的主动脉中建立VSMCs原代培养。在ArKO细胞中，逆转录聚合酶链反应证实芳香化酶细胞色素P450 mRNA表达缺失；Western blotting显示雌激素受体蛋白表达正常。ArKO细胞对血清或血小板衍生生长因子- bb的增殖反应低于WT细胞；17 -雌二醇（e - 2,10 nmol/L）增强了ArKO细胞对血小板衍生生长因子- bb的反应，抑制了WT细胞的反应。E-2在WT细胞中抑制丝裂原活化蛋白激酶ERK1/2的活性，而在ArKO细胞中没有抑制作用。肿瘤坏死因子- α引起的凋亡相关死亡在ArKO细胞中高于WT细胞；这种作用在ArKO中被E-2减弱。在两性中，ArKO和WT在VSMC增殖方面存在差异。1岁雄性小鼠的主动脉形态学研究表明，ArKO的内侧平滑肌面积比同一年龄的WT小鼠少约10%。结论：内源性雌激素缺乏可减少VSMCs的增殖并增加凋亡相关死亡；外源性E-2纠正了这些异常。
Background - Altered proliferation and death of vascular smooth muscle cells (VSMCs) are important mechanisms in vascular growth and remodeling. This study examined the effect of endogenous estrogens on VSMC proliferation.Methods and Results - An estrogen-deficient animal model, the aromatase-knockout (ArKO) mouse, was used. Primary cultures of VSMCs were established from aortas of 11-week-old male and female ArKO and wild-type ( WT) mice. In ArKO cells, the absence of aromatase cytochrome P450 mRNA expression was demonstrated by reverse transcription polymerase chain reaction; Western blotting showed normal expression of estrogen receptor protein. Proliferative responses to serum or platelet-derived growth factor-BB were lower in ArKO than WT cells; 17beta-estradiol (E-2, 10 nmol/L) enhanced the response to platelet-derived growth factor-BB in ArKO cells but inhibited the response in WT cells. E-2 inhibited activity of mitogen-activated protein kinase ERK1/2 in WT but not ArKO cells. Apoptosis-related death caused by tumor necrosis factor-alpha was greater in ArKO than in WT cells; this effect in ArKO was attenuated by E-2. Differences in VSMC proliferation between ArKO and WT occurred in both sexes. Morphological studies in aortas derived from male mice at 1 year of age demonstrated that medial smooth muscle area was approximate to 10% less in ArKO than WT mice at this age.Conclusions - Deficiency of endogenous estrogens reduces proliferation and enhances apoptosis-related death in VSMCs; exogenous E-2 corrects these abnormalities.