Marques-Lopes Jose, Van Kempen Tracey, Waters Elizabeth M, Pickel Virginia M, Iadecola Costantino, Milner Teresa A
Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, 10065.
J Comp Neurol. 2014 Sep 1;522(13):3075-90. doi: 10.1002/cne.23569.
The incidence of hypertension increases after menopause. Similar to humans, "slow-pressor" doses of angiotensin II (AngII) increase blood pressure in young males, but not in young female mice. However, AngII increases blood pressure in aged female mice, paralleling reproductive hormonal changes. These changes could influence receptor trafficking in central cardiovascular circuits and contribute to hypertension. Increased postsynaptic N-methyl-D-aspartate (NMDA) receptor activity in the hypothalamic paraventricular nucleus (PVN) is crucial for the sympathoexcitation driving AngII hypertension. Estrogen receptors β (ERβs) are present in PVN neurons. We tested the hypothesis that changes in ovarian hormones with age promote susceptibility to AngII hypertension, and influence NMDA receptor NR1 subunit trafficking in ERβ-containing PVN neurons. Transgenic mice expressing enhanced green fluorescent protein (EGFP) in ERβ-containing cells were implanted with osmotic minipumps delivering AngII (600 ng/kg/min) or saline for 2 weeks. AngII increased blood pressure in 2-month-old males and 18-month-old females, but not in 2-month-old females. By electron microscopy, NR1-silver-intensified immunogold (SIG) was mainly in ERβ-EGFP dendrites. At baseline, NR1-SIG density was greater in 2-month-old females than in 2-month-old males or 18-month-old females. After AngII infusion, NR1-SIG density was decreased in 2-month-old females, but increased in 2-month-old males and 18-month-old females. These findings suggest that, in young female mice, NR1 density is decreased in ERβ-PVN dendrites thus reducing NMDA receptor activity and preventing hypertension. Conversely, in young males and aged females, NR1 density is upregulated in ERβ-PVN dendrites and ultimately leads to the neurohumoral dysfunction driving hypertension.
绝经后高血压的发病率会升高。与人类相似，“低剂量升压型”血管紧张素II（AngII）可使年轻雄性小鼠血压升高，但对年轻雌性小鼠无效。然而，AngII会使老年雌性小鼠血压升高，这与生殖激素变化情况相似。这些变化可能会影响中枢心血管回路中的受体转运，并导致高血压。下丘脑室旁核（PVN）中突触后N-甲基-D-天冬氨酸（NMDA）受体活性增加对于交感神经兴奋驱动的AngII高血压至关重要。雌激素受体β（ERβs）存在于PVN神经元中。我们验证了这样一个假说，即随着年龄增长卵巢激素的变化会促使机体对AngII高血压易感，并影响含ERβ的PVN神经元中NMDA受体NR1亚基的转运。对在含ERβ的细胞中表达增强型绿色荧光蛋白（EGFP） 的转基因小鼠植入渗透微型泵，持续2周给予AngII（600 ng/kg/分钟）或生理盐水。AngII使2个月大的雄性小鼠和18个月大的雌性小鼠血压升高，但对2个月大的雌性小鼠无效。通过电子显微镜观察，NR1-银增强免疫金（SIG）主要位于ERβ-EGFP树突中。在基线时，2个月大的雌性小鼠中NR1-SIG密度高于2个月大的雄性小鼠或18个月大的雌性小鼠。输注AngII后，2个月大的雌性小鼠中NR1-SIG密度降低，但2个月大的雄性小鼠和18个月大的雌性小鼠中该密度增加。这些发现表明，在年轻雌性小鼠中，ERβ-PVN树突中的NR1密度降低，从而降低NMDA受体活性并预防高血压。相反，在年轻雄性小鼠和老年雌性小鼠中，ERβ-PVN树突中的NR1密度上调，最终导致驱动高血压的神经体液功能障碍。
