Age-dependent blood pressure elevation is due to increased vascular smooth muscle tone mediated by G-protein signalling.
Age-dependent blood pressure elevation is due to increased vascular smooth muscle tone mediated by G-protein signalling.
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DOI：
10.1093/cvr/cvv249
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发表时间：
2016
影响因子：
10.8
通讯作者：
A. Wirth;Shengpeng Wang;M. Takefuji;Cong Tang;Till F. Althoff;F. Schweda;N. Wettschureck;S. Offermanns
中科院分区：
文献类型：
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作者：
A. Wirth;Shengpeng Wang;M. Takefuji;Cong Tang;Till F. Althoff;F. Schweda;N. Wettschureck;S. Offermanns
目的动脉高血压是心血管疾病的主要危险因素。肾脏及其利钠功能是解释高血压发病机制的流行模型的中心;然而，大多数患者血压升高的潜在机制仍不清楚。高血压的发展与年龄密切相关，这种血压升高通常在生命的第四个十年加速。年龄依赖性血压升高的原因知之甚少。本研究旨在了解促收缩G蛋白介导的血管平滑肌信号通路在年龄依赖性高血压中的作用。方法和结果与中年人相似，我们在1岁的小鼠中观察到血压水平升高，而没有任何证据表明血管僵硬度增加，肾功能受损或内分泌异常。高血压老年小鼠表现出内皮功能障碍的迹象，并具有增加的血管形成的活性氧（ROS）和升高的内皮ET-1表达。ETA受体阻断、编码ETA受体的基因的平滑肌特异性失活以及通过使用他莫昔芬诱导的平滑肌特异性条件性敲除小鼠模型诱导平滑肌特异性Gα12/Gα13、Gαq/Gα11或LARG缺陷而急性破坏下游信号传导，可使ETA依赖性高血压正常化。诱导平滑肌特异性ETA受体缺陷使老年小鼠的血压正常化，尽管持续存在内皮功能障碍的迹象。结论血管紧张素Ⅱ依赖性血压升高是由于血管平滑肌细胞促收缩信号的高度可逆激活，表明血管张力增加可能是高血压发展的主要因素。
AIMS Arterial hypertension is a major risk factor for cardiovascular diseases. The kidney and its natriuretic function are in the centre of the prevailing models to explain the pathogenesis of hypertension; however, the mechanisms underlying blood pressure elevation remain unclear in most patients. Development of hypertension is strongly correlated with age, and this blood pressure increase typically accelerates in the fourth decade of life. The cause of age-dependent blood pressure elevation is poorly understood. This study aims to understand the role of procontractile G-protein-mediated signalling pathways in vascular smooth muscle in age-dependent hypertension. METHODS AND RESULTS Similar to humans at mid-life, we observed in 1-year-old mice elevated blood pressure levels without any evidence for increased vessel stiffness, impaired renal function, or endocrine abnormalities. Hypertensive aged mice showed signs of endothelial dysfunction and had an increased vascular formation of reactive oxygen species (ROS) and elevated endothelial ET-1 expression. Age-dependent hypertension could be normalized by ETA receptor blockade, smooth muscle-specific inactivation of the gene encoding the ETA receptor, as well as by acute disruption of downstream signalling via induction of smooth muscle-specific Gα12/Gα13, Gαq/Gα11, or LARG deficiency using tamoxifen-inducible smooth muscle-specific conditional mouse knock-out models. Induction of smooth muscle-specific ETA receptor deficiency normalized the blood pressure in aged mice despite the continuous presence of signs of endothelial dysfunction. CONCLUSION Age-dependent blood pressure elevation is due to a highly reversible activation of procontractile signalling in vascular smooth muscle cells indicating that increased vascular tone can be a primary factor in the development of hypertension.