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.

尽管小血管疾病（SVD）的后果是大脑毁灭性的，但没有特定的 目前的治疗。了解基础和可能用于防止SVD的机制的知识 它的影响包括中风和认知缺陷，非常有限。大脑副群artios是 SVD的重要电阻容器和优先目标。高血压是领先的风险因素 SVD。由于尚不清楚的原因，高血压是中风的危险因素，而不是心肌 尽管脑肾素 - 血管紧张素 - 醛固酮系统（RAAS）有助于高血压，但它是 不知道它是否也影响局部脉管系统。从这个意义上讲，脑血管可能会遭受 血管内压力增加以及在脑raas激活过程中的局部影响。我们的整体 假设是脑循环受中央raas的影响，并且内皮过氧组合体 增生剂激活的受体-γ（PPARγ）可以防止这种影响。我们提出了两个具体目标。目的 1使用两个模型来确定大脑RAAS的激活是否影响 脑动脉和副型动脉。一个是Doca-Salt模型的最新变体， 其特征是激活脑RAA，但抑制周围RAA。在第二个 脑RAAS通过遗传操纵激活。初步数据表明中央RAAS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 用于脑视频。 AIM 2将确定内皮PPARγ是否可以防止中央RAAS诱导 通过包括抑制血管紧张素II受体的机制变化，氧化应激和 Rho激酶的Rock2同工型。飞行员数据也支持此目标。这些研究的前提很好 在此RFA的目标中，重点是高血压期间SVD的新型机制。这 模型表现出使它们代表更大比例的具有必不可少的人的功能 与更常见的方法相比，高血压。飞行员数据揭示了血管异质性 高血压期间大脑循环的敏感性提高。总而言之 SVD的很棒，但是我们对潜在的血管生物学的理解以及高血压对 使用创新的模型和方法，拟议的工作将填补空白 在文献和科学界在我们的理解中所必需的进步确定 SVD，血管生物学以及高血压对脑脉管系统的影响。这个研究领域有 毫无疑问，与全球健康相关。我们分享专业知识和资源的重点 SVD的机制，具有独特的模型，方法和概念。