Central RAAS and Brain Small Vessel Disease

中枢 RAAS 和脑小血管疾病

• 批准号: 9751992
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751992
• 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; 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.

尽管小血管病（SVD）对大脑造成的后果是毁灭性的，但目前还没有具体的治疗方法。 目前的治疗方法。了解潜在并可能用于预防 SVD 的机制 其影响（包括中风和认知缺陷）非常有限。脑实质小动脉是 重要的抵抗血管和 SVD 的优先目标。高血压是主要危险因素 SVD。由于尚不清楚的原因，高血压是中风的一个比心肌梗死更大的危险因素。 梗塞。尽管大脑肾素-血管紧张素-醛固酮系统 (RAAS) 会导致高血压，但它 不知道它是否也影响局部脉管系统。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大脑 RAAS 激活期间的局部效应。我们的整体 假设是脑循环受到中枢 RAAS 的影响，并且内皮过氧化物酶体 增殖物激活受体-γ (PPARγ) 可防止此类影响。我们提出两个具体目标。目的 1 使用两个模型来确定大脑 RAAS 的激活是否会影响大脑的功能、结构或机制 脑动脉和实质小动脉。一种是 DOCA-盐模型的最新变体， 其特征是激活大脑 RAAS，但抑制外周 RAAS。在第二个中， 大脑 RAAS 是通过基因操作激活的。初步数据表明 RAAS 的主要影响选择 信号通路、血管舒缩调节和血管结构。有趣的是，这些影响是特定的 对于脑血管。目标 2 将确定内皮 PPARγ 是否可以预防中枢 RAAS 诱导的 通过抑制血管紧张素 II 受体、氧化应激和 Rho 激酶的 ROCK2 亚型。试点数据也支持这一目标。这些研究的前提非常吻合 在本次 RFA 的目标范围内，重点关注高血压期间 SVD 的新机制。这 模型所表现出的特征使它们能够代表更大比例的具有基本能力的人 与更常见的方法相比。试点数据揭示了血管异质性 有助于高血压期间大脑循环的易感性增加。总结一下，影响 SVD 的研究固然重要，但我们对潜在血管生物学以及高血压对健康的影响的了解 脑血管系统缺乏。使用创新模型和方法，拟议的工作将填补空白 文献和科学界认为我们的理解需要取得进展 SVD、血管生物学以及高血压对脑血管系统的影响。该研究领域有 与全球健康有着无可置疑的相关性。我们分享专业知识和资源，支持重点关注 SVD 机制具有独特的模型、方法和概念。