Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1837-43. doi: 10.1161/ATVBAHA.112.300752. Epub 2013 Jun 6.
The proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in vascular diseases, such as atherosclerosis and restenosis, after percutaneous coronary intervention. Many studies have shown that estrogen inhibits VSMC proliferation in response to vascular injury in the mouse carotid injury model. However, the mechanisms that mediate these effects remain unclear. Here, we investigated the mechanisms by which estrogen inhibits VSMC proliferation.
We established a novel transgenic mouse line, referred to as the disrupting peptide mice, in which rapid estrogen receptor (ER)-mediated signaling is abolished by overexpression of a peptide that prevents the ER from forming a signaling complex necessary for rapid signaling. Carotid artery VSMCs from disrupting peptide mice or littermate wild-type female mice were obtained by the explant method. In VSMCs derived from wild-type mice, estrogen significantly inhibited VSMC proliferation. Phosphorylation levels of Akt and extracellular regulated kinase induced by platelet derived growth factor were significantly inhibited by estrogen pretreatment. Estrogen enhanced complex formation between ERα and protein phosphatase 2A (PP2), and enhanced PP2A activity. The blockade of PP2A activity abolished the estrogen-induced antiproliferative effect on VSMCs. In contrast, none of these effects of estrogen observed in the wild-type VSMCs were observed in VSMCs derived from disrupting peptide mice. These results support that rapid, non-nuclear ER signaling is required for estrogen-induced inhibition of VSMC proliferation, and further that PP2A activation by estrogen mediates estrogen-induced antiproliferative effects.
These findings support that PP2A activation via rapid, non-nuclear ER signaling may be a novel target for therapeutic approaches to inhibit VSMC proliferation, which plays a central role in atherosclerosis and restenosis.
血管平滑肌细胞（VSMCs）的增殖在经皮冠状动脉介入治疗后发生的血管疾病（如动脉粥样硬化和再狭窄）中起着关键作用。许多研究表明，雌激素在小鼠颈动脉损伤模型中抑制血管损伤后 VSMC 的增殖。然而，介导这些作用的机制尚不清楚。在这里，我们研究了雌激素抑制 VSMC 增殖的机制。
我们建立了一种新的转基因小鼠品系，称为破坏肽小鼠，其中通过过表达一种阻止雌激素受体（ER）形成用于快速信号转导的必需信号复合物的肽来消除快速 ER 介导的信号。通过组织培养法获得破坏肽小鼠或同窝野生型雌性小鼠的颈动脉 VSMCs。在来自野生型小鼠的 VSMCs 中，雌激素显著抑制 VSMC 的增殖。血小板衍生生长因子诱导的 Akt 和细胞外调节激酶的磷酸化水平被雌激素预处理显著抑制。雌激素增强了 ERα 和蛋白磷酸酶 2A（PP2）之间的复合物形成，并增强了 PP2A 活性。阻断 PP2A 活性消除了雌激素对 VSMC 的抗增殖作用。相比之下，在破坏肽小鼠的 VSMCs 中没有观察到野生型 VSMCs 中观察到的雌激素的这些作用。这些结果支持快速的、非核的 ER 信号是雌激素诱导的 VSMC 增殖抑制所必需的，并且进一步支持雌激素通过激活蛋白磷酸酶 2A（PP2）介导雌激素诱导的抗增殖作用。
这些发现支持通过快速的、非核的 ER 信号激活 PP2A 可能是抑制 VSMC 增殖的新的治疗靶点，VSMC 增殖在动脉粥样硬化和再狭窄中起着核心作用。
