Central RAAS and Brain Small Vessel Disease

尽管小血管疾病(SVD)对大脑的影响是毁灭性的，但没有明确的 目前的治疗方法。关于预防SVD的基础和可能用于预防SVD的机制的知识 而且它的影响，包括中风和认知缺陷，是非常有限的。脑实质小动脉是 SVD的重要阻力血管和优先靶点。高血压是高血压的主要危险因素。 Svd。原因尚不清楚，高血压是中风的更大风险因素，而不是心肌梗死。 脑梗塞。虽然大脑肾素-血管紧张素-醛固酮系统(RAAS)对高血压有贡献，但它是 尚不清楚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这两种影响 在激活大脑RAAS的过程中，血管内压增加以及局部效应。我们的整体 假说认为大脑循环受中枢RAAS和内皮过氧化物酶的影响 增殖物激活受体γ(PPARγ)对这种作用有保护作用。我们提出了两个具体目标。目标 1使用两个模型来确定大脑RAAS的激活是否影响大脑的功能、结构或机制 脑动脉和脑实质小动脉。一种是DOCA-SALT模型的最新变体， 特点是激活了大脑RAAS，但抑制了外周RAAS。在第二种情况下， 大脑RAAS是通过基因操作激活的。初步数据显示，中央RAAS影响选择 信号通路、血管运动调节和血管结构。有趣的是，这些影响是特定的。 对于脑血管来说。AIM 2将确定内皮PPARγ是否对中枢RAAS诱导的损伤具有保护作用 血管变化的机制包括抑制血管紧张素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符合 在本RFA的目标范围内，重点研究高血压期间SVD的新机制。这个 模特展示的特征使它们代表了更大比例的有必要的人 高血压与更常见的治疗方法相比。试点数据揭示了血管的异质性 有助于在高血压期间增加大脑循环的易感性。总而言之，其影响 SVD是很好的，但我们对潜在的血管生物学和高血压对 脑血管系统缺乏。利用创新的模式和方法，拟议的工作将填补空白 在文献中和科学界确定的关于我们理解中所需的进步 SVD、血管生物学以及高血压对脑血管系统的影响。这一研究领域有 与全球健康的相关性毋庸置疑。我们的专业知识和资源共享支持专注于 具有独特的模型、方法和概念的奇异值分解的机制。

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.