Hypertension and neurovascular dysfunction

高血压和神经血管功能障碍

基本信息

批准号：
9915965
负责人：
Costantino Iadecola
金额：
$ 46.61万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915965
关键词：
Address Adult Aging Angiotensin II Antihypertensive Agents Basement membrane Blood - brain barrier anatomy Blood Vessels Bone Marrow Bone Marrow Transplantation Brain Cell model Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Chimera organism Chronic Cognition Cognitive Consensus Data Dementia Dichloromethylene Diphosphonate Dose Electron Microscopy Encapsulated Endothelial Cells Functional disorder Gene Deletion Genes Genetic Genetic Models Goals Human Hypertension Impaired cognition Infusion procedures Knowledge Life Link Liposomes Maintenance Mediating Modeling Molecular Morbidity - disease rate Mus NADPH Oxidase Neurons Organ Oxidative Stress Pathogenicity Peptides Perfusion Pericytes Positioning Attribute Predisposition Prevention therapy Process Production Proteins Reactive Oxygen Species Receptor, Angiotensin, Type 1 Regulation Risk Risk Factors Role Side Source Stress Stroke Structure Testing Tight Junctions Uncertainty United States National Institutes of Health Vascular Endothelium Vesicle aged blood lead blood-brain barrier function brain dysfunction burden of illness cellular targeting cerebrovascular cognitive function defined contribution experimental study hypertension treatment insight interest ischemic injury macrophage monocyte mortality neurovascular normotensive novel novel strategies prevent public health relevance receptor response stroke risk therapeutic target trafficking

项目摘要

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.

描述（由适用提供）：高血压是中风和痴呆症的主要危险因素，但是介导其对大脑有害影响的机制仍然很少了解。高血压会损害大脑对中风和认知障碍的敏感性的脑血管的结构和功能。特别是，高血压破坏了确保足够脑灌注的关键稳态机制，促进血管不足和脑功能障碍。在通过输注低剂量血管紧张素II（血管菌）的高血压中，与人类高血压有关的肽或在遗传基础上（BPH小鼠）终生高血压（BPH小鼠）的小鼠中，脑血管功能障碍是由Angii 1型受体（AT1R）激活的激活而导致Angii类型受体的激活（AT1R），从而导致氧化不良。 ANGII的细胞靶标，其在血管壁中的效应子以及神经血管功能障碍对认知的影响尚待建立，并且具有很大的转化相关性。血管周围巨噬细胞（PVM）是骨髓衍生的细胞，它们位于血管周空间中，密切应用到脑血管基底膜和Express AT1R和NOX2，因此，有助于脑血管功能障碍受Angii依赖性依赖性依赖性高血压引起的脑血管功能障碍。该应用的中心假设是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，我们将确定感染了2周的Angii是否越过血脑屏障并在血管周空间中达到PVM。其次，我们将确定是否需要PVM，即Angii输注引起的脑血管和认知改变。第三，我们将确定PVM中的AT1R和NOX2是否参与功能障碍。在平行研究中，我们还将检查PVM在患有终身高血压（BPH小鼠）的年轻小鼠和老年小鼠中观察到的PVM在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与骨髓嵌合体和遗传模型相结合研究神经血管调节，以解决感兴趣基因的细胞特异性条件缺失。拟议的研究得出的发现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明显差距，并将提供原则上的证明，即PVM可能是高血压对大脑造成毁灭性作用的治疗靶标。