Hypertension and neurovascular dysfunction

 描述(申请人提供)：高血压是中风和痴呆症的主要危险因素，但其对大脑的有害影响的机制仍然知之甚少。高血压损害了脑血管的结构和功能，增加了大脑对中风和认知障碍的易感性。特别是，高血压扰乱了确保充足脑血流的关键动态平衡机制，促进了血管功能不全和脑功能障碍。在注射小剂量血管紧张素II(AngII)诱导的高血压中，或在遗传基础上终身高血压的小鼠(BPH小鼠)中，脑血管功能障碍是由AngiI1型受体(AT1R)激活介导的，AT1R导致含有NOX2的NADPH氧化酶产生血管氧化应激。血管紧张素转换酶的细胞靶点(S)、其在血管壁的效应物以及神经血管功能障碍对认知的影响仍有待确定，具有很大的翻译相关性。血管周围巨噬细胞(PVM)是一种骨髓来源的细胞，存在于血管周围空间，与脑血管基底膜紧密贴近，表达AT1R和NOX2，因此在血管依赖性高血压引起的脑血管功能障碍中具有重要作用。这一应用的中心假设是PVM是高血压引起的脑血管和认知功能障碍的关键细胞。为此，首先我们将确定输注2周的Angii是否越过血脑屏障，到达血管周围空间的PVM。其次，我们将确定PVM是否是血管紧张素转换酶抑制剂引起的脑血管和认知改变所必需的。第三，我们将确定PVM中的AT1R和NOX2是否参与了功能障碍。在平行研究中，我们还将研究PVM在患有终生高血压的年轻和老年小鼠(BPH小鼠)观察到的脑血管和认知功能障碍中的作用。为了实现这些目标，我们将使用最先进的方法结合骨髓嵌合体和细胞特异性有条件删除感兴趣基因的遗传模型来研究神经血管调节。从拟议的研究中得出的结果将填补 我们对高血压引起的脑功能障碍的细胞机制的理解存在明显的差距，这将为PVM可能成为高血压对大脑破坏性影响的治疗靶点提供原则证明。

 DESCRIPTION (provided by applicant): Hypertension is a leading risk factor for stroke and dementia, but the mechanisms mediating its deleterious effects on the brain remain poorly understood. Hypertension damages the structure and function of cerebral blood vessels increasing the susceptibility of the brain to stroke and cognitive impairment. In particular, hypertension disrupts critical homeostatic mechanisms that assure adequate cerebral perfusion, promoting vascular insufficiency and brain dysfunction. In the hypertension induced by infusion of low doses of angiotensin II (AngII), a peptide involved in human hypertension, or in mice with life-long hypertension on genetic basis (BPH mice), the cerebrovascular dysfunction is mediated by activation of AngII type 1 receptors (AT1R) resulting in vascular oxidative stress produced by a Nox2-containing NADPH oxidase. The cellular target(s) of AngII, its effectors in the vascular wall and the impact of the neurovascular dysfunction on cognition remain to be established and are of great translational relevance. Perivascular macrophages (PVM) are bone marrow derived cells residing in the perivascular space in close apposition to the cerebrovascular basement membrane and express AT1R and Nox2 and, as such, are well positioned to contribute to the cerebrovascular dysfunction induced by AngII-dependent hypertension. The central hypothesis of this application is that PVM are critical cells for the cerebrovascular and cognitive dysfunctio induced by hypertension. To this end, first we will establish whether AngII, infused for 2 weeks, crosses the blood-brain barrier and reaches the PVM in the perivascular space. Second, we will determine whether PVM are required for the cerebrovascular and cognitive alterations induced by AngII infusion. Third, we will determine whether AT1R and Nox2 in PVM are involved in the dysfunction. In parallel studies we will also examine the role of PVM in the cerebrovascular and cognitive dysfunction observed in young and aged mice with life-long hypertension (BPH mice). To achieve these goals we will use state-of-the-art approaches to study neurovascular regulation in combination with bone marrow chimeras and genetic models for cell specific conditional deletion of genes of interest. The findings derived from the proposed studies will fill an obvious gap in our understanding of the cellular mechanisms of the brain dysfunction induced by hypertension, and will provide proof-of-principle that PVM may be a therapeutic target for the devastating effects of hypertension on the brain.