Female mice are protected from impaired parenchymal arteriolar TRPV4 function and impaired cognition in hypertension.
Female mice are protected from impaired parenchymal arteriolar TRPV4 function and impaired cognition in hypertension.
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雌性小鼠可免受实质小动脉 TRPV4 功能受损和高血压认知受损的影响。
DOI：
10.1152/ajpheart.00481.2022
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Dorrance,AnneM
中科院分区：
文献类型：
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作者：
Chambers,LauraC;Yen,Martina;Jackson,WilliamF;Dorrance,AnneM
高血压是脑小血管疾病的主要可改变的危险因素。我们的实验室已经表明，脑实质小动脉（PA）的内皮依赖性舒张依赖于瞬时受体电位香草酸4（TRPV 4）的激活，这一途径在高血压中受损。这种受损的扩张与认知缺陷和神经炎症有关。流行病学证据表明，患有中年高血压的女性患痴呆症的风险增加，而年龄匹配的男性则不存在，尽管对此负责的机制尚不清楚。本研究旨在确定年轻高血压小鼠的性别差异，为将来确定中年性别差异奠定基础。我们测试了这样的假设，即年轻的高血压雌性小鼠将受到保护，从受损的TRPV 4介导的PA扩张和认知功能障碍观察到的雄性小鼠。将血管紧张素II（ANG II）填充的渗透微型泵（800 ng/kg/min，4周）植入16- 19周龄雄性C56 BL/6小鼠。匹配的雌性小鼠接受800 ng/kg/min或1，200 ng/kg/min ANG II。假手术小鼠作为对照。ANG II治疗的雄性小鼠和1，200 ng ANG II治疗的雌性小鼠与性别匹配的假手术相比，收缩压升高。高血压雄性小鼠对TRPV 4激动剂GSK 1016790 A（10−9-10− 5 M）的PA扩张反应受损，这与认知功能障碍和神经炎症有关，重现了我们以前的发现。高血压雌性小鼠表现出正常的TRPV 4介导的PA扩张和认知完整。雌性小鼠也比雄性小鼠表现出更少的神经炎症迹象。确定高血压患者脑血管健康的性别差异对于制定有效的女性治疗策略至关重要。新&值得注意的是血管性痴呆是一个重要的公共卫生问题，生物性别对痴呆发展的影响尚未得到很好的理解。TRPV 4通道是脑实质小动脉功能和认知的重要调节因子。高血压损害雄性啮齿动物TRPV 4介导的扩张和记忆。这里提供的数据表明，女性在高血压期间保护TRPV 4扩张受损和认知功能障碍。这些数据推进了我们对生物性别对高血压患者脑血管健康影响的理解。
Hypertension is a leading modifiable risk factor for cerebral small vessel disease. Our laboratory has shown that endothelium-dependent dilation in cerebral parenchymal arterioles (PAs) is dependent on transient receptor potential vanilloid 4 (TRPV4) activation, and this pathway is impaired in hypertension. This impaired dilation is associated with cognitive deficits and neuroinflammation. Epidemiological evidence suggests that women with midlife hypertension have an increased dementia risk that does not exist in age-matched men, though the mechanisms responsible for this are unclear. This study aimed to determine the sex differences in young, hypertensive mice to serve as a foundation for future determination of sex differences at midlife. We tested the hypothesis that young hypertensive female mice would be protected from the impaired TRPV4-mediated PA dilation and cognitive dysfunction observed in male mice. Angiotensin II (ANG II)-filled osmotic minipumps (800 ng/kg/min, 4 wk) were implanted in 16- to 19-wk-old male C56BL/6 mice. Age-matched female mice received either 800 ng/kg/min or 1,200 ng/kg/min ANG II. Sham-operated mice served as controls. Systolic blood pressure was elevated in ANG II-treated male mice and in 1,200 ng ANG II-treated female mice versus sex-matched shams. PA dilation in response to the TRPV4 agonist GSK1016790A (10−9–10−5M) was impaired in hypertensive male mice, which was associated with cognitive dysfunction and neuroinflammation, reproducing our previous findings. Hypertensive female mice exhibited normal TRPV4-mediated PA dilation and were cognitively intact. Female mice also showed fewer signs of neuroinflammation than male mice. Determining the sex differences in cerebrovascular health in hypertension is critical for developing effective therapeutic strategies for women.NEW & NOTEWORTHYVascular dementia is a significant public health concern, and the effect of biological sex on dementia development is not well understood. TRPV4 channels are essential regulators of cerebral parenchymal arteriolar function and cognition. Hypertension impairs TRPV4-mediated dilation and memory in male rodents. Data presented here suggest female sex protects against impaired TRPV4 dilation and cognitive dysfunction during hypertension. These data advance our understanding of the influence of biological sex on cerebrovascular health in hypertension.