Circumventricular Organs: Gender and Hypertension

描述（由申请方提供）：已在人类和动物模型中充分描述了高血压和心血管疾病发生的性别差异。已知低剂量AngII输注通过CNS作用于脑干和下丘脑中的室周器官诱导神经源性高血压。越来越多的证据表明AngII中枢和外周作用涉及活性氧的活化。同样，雌激素和睾酮的中枢外周研究表明，它们的许多心血管相关作用可能与它们对活性氧（ROS）和一氧化氮（NO）产生的调节有关。我们实验室的最新数据表明，低剂量输注AngII导致WT雄性小鼠高血压，但在完整的WT雌性小鼠中没有。此外，我们有新的初步数据表明，血管紧张素II诱导的高血压在男性中被阻断的肾上腺素受体fluorescent的中央输注和超氧化物歧化酶（SOD）模拟tempol的中央输注，男性显示更高水平的细胞内活性氧在CVO神经元后血管紧张素II长期输注比女性。该提案将使用AngII高血压关键脑室周围器官的脑干切片，最先进的成像技术，实时RT-PCR，腺，腺载体基因转移和有意识血压记录的遥测测量，以检验性和性类固醇通过与脑干的室周器官内的自由基和NO产生途径的相互作用来调节AngII的中枢作用的一般假设，下丘脑该假设将通过4个具体目标进行检验：具体目标1。确定nNOS和SOD在AngII诱导的雄性和雌性小鼠脑干和前脑CVO脑切片中[Ca ++] i增加中的作用。具体目标二：确定性别和性类固醇对AngII诱导的雄性和雌性小鼠脑干和前脑CVO中细胞内ROS释放的影响。具体目标3：测定性激素和性类固醇对雄性和雌性小鼠脑干和前脑CVOs中SOD、nNOS和AT 1受体表达的影响。具体目标4：确定WT男性和女性中SOD和nNOS在AngII诱导的高血压中的作用。

DESCRIPTION (provided by applicant): Sex differences in the development of hypertension and cardiovascular disease have been well described in humans and in animal models. Low dose AngII infusion is known to induce a neurogenic hypertension via CNS actions on circumventricular organs in the brainstem and hypothalamus. An increasing body of evidence has shown that Angll central and peripheral effects involve activation of reactive oxygen. Similarly, central peripheral studies with estrogen and testosterone have shown that many of their cardiovascular related effects may be related their modulation of the generation of reactive oxygen species (ROS) and nitric oxide (NO). Recent data from our laboratory have shown that low-dose infusion of AngII results in hypertension WT male mice but not in intact WT females. Further, we have new preliminary data showing that AngII induced hypertension in males is blocked by central infusions of the adrogen receptor flutamide and by central infusion of the superoxide dismutase (SOD) mimetic tempol and that males show greater levels of intracellular ROS in CVO neurons following Ang II long-term infusion than females. This proposal will use brainstem slices of circumventricular organs key to AngII hypertension, state-of-the-art imaging techniques, real-time RT-PCR, adeno-vector gene transfer and telemetry measurements of conscious blood pressure recordings to test the general hypothesis that sex and sex steroids modulate the central actions of Angll via interactions with free radical and NO generating pathways within the circumventricular organs of the brainstem and hypothalamus. This hypothesis will be tested with 4 specific aims: Specific Aim 1. Determine the roles of nNOS and SOD on AngII induced increases in [Ca++]i in the brainstem and forebrain CVO brain slices from male and female mice. Specific Aim 2: Determine the effects of sex and sex steroids on AngII induced release of intracellular ROS in the brainstem and forebrain CVOs of male and female mice. Specific Aim 3: Determine the effects of sex and sex steroids on expression of SOD, nNOS and AT1 receptors in the brainstem and forebrain CVOs of males and females mice. Specific Aim 4: Determine the role of SOD and nNOS in AngII induced hypertension in WT males and females.