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G蛋白耦联型雌激素受体敲除大鼠的应激性高血压反应

罗萍¹, 吴美美¹, 高坡¹, 高婷¹, 董莉¹, 丁晓唯¹, 孟佑强¹, 钱佳红¹, 张国花¹, 戎伟芳^1,2,*

¹上海交通大学医学院同仁医院/虹桥国际医学研究院，基础医学院生理学教研室，上海 200025；²宁夏医科大学颅脑疾病重点实验室，银川 750004

摘要

大量研究显示雌激素通过传统核受体ERα或ERβ以及新型膜受体——G蛋白耦联雌激素受体(G protein coupled estrogen receptor, Gper)对心血管系统起多方面保护作用。然而，文献报道的Gper基因敲除(Gper-knockout, Gper-KO)小鼠心血管系统表型差异很大。本研究旨在揭示Gper-KO对大鼠动脉血压和心率的影响。Gper-KO SD大鼠系采用CRISPR-Cas9基因编辑技术制备。我们对10周龄雄性Gper-KO大鼠(n = 6)、12周龄雌性Gper-KO大鼠(n = 6)以及同龄野生型(wild type, WT)大鼠(雌雄各6只)，在清醒和束缚制动条件下进行无创检测尾动脉血压，连续检测8~9天，继而又在戊巴比妥麻醉下直接测量股动脉血压。WT雄性大鼠的尾动脉血压在第1至第4天略高于第5至第9天，表明在实验初期束缚应激引起的交感系统兴奋使大鼠血压升高，随着大鼠对束缚应激的逐步适应，其血压恢复至正常水平。雄性或雌性Gper-KO大鼠的动脉血压在实验初期都高于WT组(雄性大鼠：第1天至第5天；雌性大鼠：第1天至第3天)，而随后几天的血压与WT组之间没有明显差异。雄性Gper-KO大鼠的心率高于雄性WT大鼠，雄性和雌性Gper-KO大鼠的体重增加值均较WT组大鼠减少。在麻醉状态下，Gper-KO组和WT组大鼠动脉血压无明显差异。以上结果表明，Gper-KO大鼠可能对应激性交感系统兴奋更为敏感，提示Gper在应激状态下的心血管功能调节中发挥重要作用。

关键词： 雌激素; G蛋白耦联型雌激素受体(Gper) ; 应激 ; 高血压 ; 交感神经系统

分类号：R331;R338;R339.5

Stress-related arterial hypertension in Gper-deficient rats

Luo Ping¹, WU Mei-Mei¹, GAO Po¹, GAO Ting¹, DONG Li¹, DING Xiao-Wei¹, MENG You-Qiang¹, QIAN Jia-Hong¹, ZHANG Guo-Hua¹, RONG Wei-Fang^1,2,*

¹Hongqiao International Institute of Medical Research, Tongren Hospital and Department of Physiology, Faculty of Basic Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China；²Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan 750004, China

Abstract

Numerous studies have demonstrated that estrogens may exert multifaceted effects on the cardiovascular system via activating the classical nuclear receptors ERα or ERβ and the novel G protein coupled estrogen receptor (Gper). However, some studies have reported inconsistent cardiovascular phenotypes in Gper-deficient mice. The current study was aimed to reveal the effects of genetic deletion of Gper on the arterial blood pressure (ABP) and heart rate in rats. Gper-deficient Sprague-Dawley rats were generated by utilizing the CRISPR-Cas9 gene-editing technique. ABP of 10-week old male (n = 6) and 12-week old female (n = 6) Gper- deficient rats and age-matched wild type (WT) rats (6 females and 6 males) were measured under awake and restrained conditions through the non-invasive tail-cuff method daily for 8 (females) or 9 days (males). In the male WT rats, ABP and heart rate were slightly higher in day 1 to 4 than those in day 5 to 9, indicative of stress-related sympathoexcitation in the first few days and gradual adaptation to the restrained stress in later days. Gper-deficient rats had significantly higher ABP initially (male: day 1 to day 5; female: day 1 to day 3) and similar ABP in later days of measurement compared with the WT rats. The heart rate of male Gper-deficient rats was consistently higher than that of the male WT rats from day 1 to day 8. Both male and female Gper-deficient rats appeared to show slower body weight gain than the WT counterparts during the study period. Under anesthesia, ABP of Gper-deficient rats was not significantly different from their WT counterparts. These results indicate that Gper-deficient rats may be more sensitive to stress-induced sympathoexcitation and highlight the importance of Gper in the regulation of the cardiovascular function in stressful conditions.

Key words: estrogens; G protein coupled estrogen receptor (Gper) ; stress ; hypertension ; sympathetic nervous system

收稿日期：2017-05-18　　录用日期：2017-06-13

通讯作者：戎伟芳　　E-mail: weifangrong@shsmu.edu.cn

DOI: 10.13294/j.aps.2017.0047

引用本文：

罗萍, 吴美美, 高坡, 高婷, 董莉, 丁晓唯, 孟佑强, 钱佳红, 张国花, 戎伟芳. G蛋白耦联型雌激素受体敲除大鼠的应激性高血压反应[J]. 生理学报 2017; 69 (5): 532-540.

Luo Ping, WU Mei-Mei, GAO Po, GAO Ting, DONG Li, DING Xiao-Wei, MENG You-Qiang, QIAN Jia-Hong, ZHANG Guo-Hua, RONG Wei-Fang. Stress-related arterial hypertension in Gper-deficient rats. Acta Physiol Sin 2017; 69 (5): 532-540