Central RAAS and Brain Small Vessel Disease

中枢 RAAS 和脑小血管疾病

• 批准号: 10405484
• 负责人: Frank M Faraci
• 金额: $ 50.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405484
• 关键词: Acetates; Address; Affect; Angiotensin II; Angiotensin II Receptor; Animal Model; Area; Biology; Blood Vessels; Brain; Cells; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Clinical; Cognitive deficits; Communities; Data; Dementia; Deoxycorticosterone; Disease; Endothelium; Essential Hypertension; Exhibits; Genetic Models; Goals; Health; Heterogeneity; Human; Human Genetics; Hypertension; Impaired cognition; Knowledge; Literature; Mechanics; Microvascular Dysfunction; Modeling; Molecular Target; Myocardial Infarction; Nitric Oxide Synthase; Oxidative Stress; PPAR gamma; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Pharmacology; Process; Protein Isoforms; Regulation; Renin-Angiotensin System; Renin-Angiotensin-Aldosterone System; Resistance; Resources; Rho-associated kinase; Risk Factors; Role; Signal Pathway; Sodium Chloride; Stroke; Structure; Testing; Variant; Vasomotor; Vasopressins; Work; arteriole; base; brain circulation; cerebral artery; cerebral microvasculature; cerebrovascular; experimental study; genetic approach; genetic manipulation; global health; innovation; interest; nervous system disorder; novel; parenchymal arterioles; pressure; prevent; vascular factor

Although the consequences of small vessel disease (SVD) are devastating for brain, there are no specific therapies at present. Knowledge of mechanisms that underlie and might potentially be used to prevent SVD and its effects, which include strokes and cognitive deficits, is very limited. Brain parenchymal arterioles are important resistance vessels and preferential targets of SVD. Hypertension is a the leading risk factor for SVD. For reasons that are not clear, hypertension is a greater risk factor for stroke than for myocardial infarction. Although the brain renin-angiotensin-aldosterone system (RAAS) contributes to hypertension, it is not known if it also affects the local vasculature. In that sense, cerebral vessels may be subjected to both increased intravascular pressure as well as local effects during activation of the brain RAAS. Our overall hypothesis is that the cerebral circulation is affected by the central RAAS and that endothelial peroxisome proliferator-activated receptor-γ (PPARγ) protects against such effects. We propose two Specific Aims. Aim 1 uses two models to determine if activation of the brain RAAS affects function, structure, or mechanics of cerebral arteries and parenchymal arterioles. One is a recent variation of the DOCA-salt model, characterized by activation of the brain RAAS, but suppression of the peripheral RAAS. In the second, the brain RAAS is activated by genetic manipulation. Preliminary data suggest the central RAAS impacts select signaling pathways, vasomotor regulation, and vascular structure. Interestingly, these effects were specific for cerebral vessels. Aim 2 will determine if endothelial PPARγ protects against central RAAS-induced vascular changes via mechanisms that include suppression of angiotensin II receptors, oxidative stress, and the ROCK2 isoform of Rho kinase. Pilot data support this Aim as well. The premise for these studies fit well within the goals of this RFA, focusing on novel mechanisms that underlie SVD during hypertension. The models exhibit features making them representative of a greater percentage of people with essential hypertension compared to more common approaches. Pilot data reveal vascular heterogeneity that contributes to increased susceptability of the brain circulation during hypertension. In summary, the impact of SVD is great, but our understanding of the underlying vascular biology and the impact of hypertension on the brain vasculature in lacking. Using innovative models and approaches, the proposed work will fill gaps identified in the literature and by the scientific community regarding needed advances in our understanding of SVD, vascular biology, and impact of hypertension on the brain vasculature. This area of study has unquestionable relevance to global health. Our sharing of expertise and resources supports a focus on mechanisms of SVD with models and approaches and concepts that are unique.

虽然小血管疾病（SVD）的后果对大脑是毁灭性的，但目前还没有具体的 治疗目前。了解SVD的基础机制和可能用于预防SVD的机制 其影响，包括中风和认知缺陷，是非常有限的。脑实质小动脉 重要的阻力血管和SVD的优先靶点。高血压是一个主要的危险因素， SVD.由于尚不清楚的原因，高血压是中风比心肌梗死更大的危险因素。 梗塞虽然脑肾素-血管紧张素-醛固酮系统（RAAS）有助于高血压，但它是高血压的一个重要组成部分。 不知道它是否也会影响局部血管系统。从这个意义上说，脑血管可能同时受到 血管内压力增加以及脑RAAS激活期间的局部效应。我们的整体 假设脑循环受中枢RAAS的影响，内皮过氧化物酶体 增殖物激活受体-γ（PPARγ）可防止这种作用。我们提出两个具体目标。目的 1使用两种模型来确定大脑RAAS的激活是否影响大脑皮层的功能、结构或力学。 脑动脉和实质小动脉。一个是DOCA-盐模型的最新变体， 其特征在于激活脑RAAS，但抑制外周RAAS。在第二 大脑RAAS是通过基因操作激活的。初步数据表明，中央RAAS的影响选择 信号通路、血管调节和血管结构。有趣的是，这些影响是特定的， 脑血管的目的2将确定内皮细胞PPARγ是否能保护中枢RAAS诱导的 通过包括抑制血管紧张素II受体、氧化应激和 Rho激酶ROCK 2亚型。试点数据也支持这一目标。这些研究的前提非常吻合 在本RFA的目标范围内，重点关注高血压期间SVD的新机制。的 模型展示的特征使它们代表了更大比例的具有基本特征的人。 高血压与更常见的方法相比。初步数据显示血管异质性， 有助于增加高血压期间脑循环的易失性。总之，影响 SVD的发生率很高，但我们对潜在的血管生物学和高血压对血管的影响的理解， 大脑血管系统缺乏。拟议的工作将利用创新的模式和方法， 在文献中和科学界确定的关于我们理解的必要进展， 血管生物学和高血压对脑血管的影响。这一研究领域有 对全球健康的重要性毋庸置疑。我们分享专业知识和资源， 奇异值分解的机制具有独特的模型、方法和概念。