Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States.
Life Sci. 2012 Oct 15;91(13-14):623-7. doi: 10.1016/j.lfs.2012.01.007. Epub 2012 Feb 2.
An increase in intracellular vascular smooth muscle cell calcium concentration (VSMC Ca(2+)) is essential for endothelin-1 (ET-1)-induced vasoconstriction. Based on previous findings that activation of the G protein-coupled estrogen receptor (GPER) inhibits vasoconstriction in response to ET-1 and regulates Ca(2+) in cultured VSMC, we investigated whether endogenous GPER regulates ET-1-induced changes in VSMC Ca(2+) and constriction of intact arteries.
Pressurized carotid arteries of GPER-deficient (GPER(0)) and wildtype (WT) mice were loaded with the calcium indicator fura 2-AM. Arteries were stimulated with the GPER-selective agonist G-1 or solvent followed by exposure to ET-1. Changes in arterial diameter and VSMC Ca(2+) were recorded simultaneously. Vascular gene expression levels of ET(A) and ET(B) receptors were determined by qPCR.
ET-1-dependent vasoconstriction was increased in arteries from GPER(0) compared to arteries from WT mice. Despite the more potent vasoconstriction to ET-1, GPER deficiency was associated with a marked reduction in the ET-1-stimulated VSMC Ca(2+) increase, suggesting an increase in myofilament force sensitivity to Ca(2+). Activation of GPER by G-1 had no effect on vasoconstriction or VSMC Ca(2+) responses to ET-1, and expression levels of ET(A) or ET(B) receptor were unaffected by GPER deficiency.
These results demonstrate that endogenous GPER inhibits ET-1-induced vasoconstriction, an effect that may be associated with reduced VSMC Ca(2+) sensitivity. This represents a potential mechanism through which GPER could contribute to protective effects of endogenous estrogen in the cardiovascular system.
细胞内血管平滑肌细胞钙离子浓度（VSMC Ca(2+)）的增加对于内皮素-1（ET-1）诱导的血管收缩至关重要。基于先前的研究发现，G 蛋白偶联雌激素受体（GPER）的激活抑制了对 ET-1 的血管收缩反应，并调节了培养的 VSMC 中的 Ca(2+)，我们研究了内源性 GPER 是否调节 VSMC Ca(2+) 和完整动脉的 ET-1 诱导的收缩。
用钙离子指示剂 fura 2-AM 加载 GPER 缺陷型（GPER(0)）和野生型（WT）小鼠的加压颈动脉。用 GPER 选择性激动剂 G-1 或溶剂刺激动脉，然后暴露于 ET-1。同时记录动脉直径和 VSMC Ca(2+) 的变化。通过 qPCR 测定血管中 ET(A)和 ET(B)受体的基因表达水平。
与 WT 小鼠的动脉相比，GPER(0)的动脉中 ET-1 依赖性血管收缩增加。尽管对 ET-1 的血管收缩作用更强，但 GPER 缺乏与 ET-1 刺激的 VSMC Ca(2+)增加显著减少有关，这表明肌丝力对 Ca(2+)的敏感性增加。G-1 激活 GPER 对 ET-1 引起的血管收缩或 VSMC Ca(2+)反应没有影响，GPER 缺乏也不影响 ET(A)或 ET(B)受体的表达水平。
这些结果表明，内源性 GPER 抑制 ET-1 诱导的血管收缩，这种作用可能与降低 VSMC Ca(2+)敏感性有关。这代表了 GPER 可能有助于内源性雌激素在心血管系统中发挥保护作用的潜在机制。
