Circumventricular Organs: Gender and Hypertension

描述（由申请人提供）：在人类和动物模型中已经很好地描述了高血压和心血管疾病发展的性别差异。已知低剂量AngII输注可通过中枢神经系统对脑干和下丘脑脑室周围器官的作用诱导神经源性高血压。越来越多的证据表明，Angll中枢和外周效应涉及活性氧的活化。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）生成的调节有关。我们实验室最近的数据表明，低剂量的AngII输注会导致WT雄性小鼠高血压，但不会导致完整的WT雌性小鼠高血压。此外，我们有新的初步数据表明，雄激素受体氟他胺的中心输注和超氧化物歧化酶（SOD）模拟酶的中心输注可以阻断雄性AngII诱导的高血压，并且在长期输注AngII后，雄性CVO神经元的细胞内ROS水平高于雌性。该提案将使用AngII高血压的关键脑干周围器官切片，最先进的成像技术，实时RT-PCR，腺载体基因转移和有意识血压记录的遥测测量来测试一般假设，即性和性类固醇通过与脑干和下丘脑的脑干周围器官内的自由基和NO生成途径的相互作用来调节Angll的中枢作用。这一假设将通过4个具体目标进行检验：测定nNOS和SOD在雄性和雌性小鼠脑干和前脑CVO脑切片AngII诱导的[Ca++]i升高中的作用。特异性目的2：确定性和性类固醇对雄性和雌性小鼠脑干和前脑CVOs中AngII诱导的细胞内ROS释放的影响。特异性目的3：测定性和性类固醇对雌雄小鼠脑干和前脑CVOs中SOD、nNOS和AT1受体表达的影响。特异性目的4：确定SOD和nNOS在WT雄性和雌性AngII诱导高血压中的作用。

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.