G 蛋白偶联雌激素受体激动剂改善雄性和雌性大鼠缺氧/复氧损伤后脑微血管功能。
G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats.
机构信息
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
出版信息
Stroke. 2013 Mar;44(3):779-85. doi: 10.1161/STROKEAHA.112.678177. Epub 2013 Jan 29.
BACKGROUND AND PURPOSE
Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro- and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein-coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. We investigated the mechanism of GPER-mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury.
METHODS
Rat cerebral penetrating arterioles from both sexes were isolated, cannulated, and pressurized. Vessel diameters were recorded by computer-aided videomicroscopy. To investigate vasomotor mechanism of the GPER agonist (G-1), several inhibitors with or without endothelial impairment were tested. Ischemia/reperfusion injury was simulated using H/RO. Vasomotor responses to adenosine triphophate after H/RO were measured with or without G-1 and compared with controls.
RESULTS
G-1 produced a vasodilatory response, which was partially dependent on endothelium-derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. Attenuation of G-1-vasodilation by the NO synthase inhibitor and endothelium-impairment were greater in vessels from female than male animals. G-1 treatment after H/RO injury fully restored arteriolar dilation to adenosine triphophate compared with controls.
CONCLUSIONS
GPER agonist elicited dilation, which was partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER agonist restored vessel function of arterioles after H/RO injury and may play an important role in the ability of estrogen to protect the cerebrovasculature against ischemia/reperfusion injury.
背景与目的
据认为，成年女性中风风险降低和严重程度降低依赖于内源性雌激素的正常水平，而雌激素是实验性脑缺血的一种已知的神经和血管保护剂。最近，一种新型 G 蛋白偶联雌激素受体（GPER，以前称为 GPR30）已被鉴定出来，可能介导雌激素的血管运动和保护作用。然而，与脑微循环中 GPER 相关的信号机制仍不清楚。我们研究了 GPER 介导的血管反应性及其在缺氧/复氧（H/RO）损伤后的血管保护作用的机制。
方法
从两性大鼠分离出脑穿透小动脉，插管并加压。通过计算机辅助视频显微镜记录血管直径。为了研究 GPER 激动剂（G-1）的血管运动机制，我们测试了几种有或没有内皮损伤的抑制剂。使用 H/RO 模拟缺血/再灌注损伤。测量 H/RO 后腺苷三磷酸的血管反应性，并与 G-1 和对照进行比较。
结果
G-1 产生了血管舒张反应，部分依赖于内皮衍生的一氧化氮（NO），但不依赖于花生四烯酸级联和内皮超极化因子。NO 合酶抑制剂和内皮损伤对 G-1 血管舒张的抑制作用在雌性动物的血管中比雄性动物更强。与对照组相比，H/RO 损伤后 G-1 处理完全恢复了对腺苷三磷酸的血管扩张作用。
结论
GPER 激动剂引起的舒张作用部分是由内皮一氧化氮途径引起的，并直接引起平滑肌细胞松弛。此外，GPER 激动剂恢复了 H/RO 损伤后小动脉的血管功能，并且可能在雌激素保护脑血管免受缺血/再灌注损伤方面发挥重要作用。
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