Lesions and loss of smooth muscle cells in brain underlies small vessel disease

大脑中平滑肌细胞的病变和损失是小血管疾病的基础

基本信息

批准号：
10527075
负责人：
ANNE JOUTEL
金额：
$ 198.93万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10527075
关键词：
3-Dimensional 4D Imaging Adolescent Affect Alzheimer&apos s Disease Animal Model Animals Area Atrophic Autopsy Basal Ganglia Birth Blood Vessels Blood capillaries Brain Brain Injuries Brain Pathology Brain imaging Brain region CADASIL Caliber Cell membrane Cells Cerebral hemisphere hemorrhage Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular system Collection Complex Computer Models Coupled Data Data Set Dementia Development Disease Disease model Distal Electrophysiology (science)Emerging Technologies Endothelial Cells Endothelium Enterobacteria phage P1 Cre recombinase Erythrocytes Functional disorder Histology Human Image Impaired cognition Infarction Inherited Ion Channel Ischemic Stroke Label Lesion LoxP-flanked allele Magnetic Resonance Imaging Measures Membrane Potentials Methodology Microelectrodes Microspheres Microvascular Dysfunction Modeling Molecular Mus NOTCH3 gene Neurobehavioral Manifestations Pathogenesis Pathology Patients Pericytes Phenocopy Play Population Preparation Property Records Regulation Reporting Resolution Rest Retina Sampling Smooth Muscle Myocytes Stroke Techniques Technology Testing Thalamic structure Time Transgenic Mice Trees Ultrasonography age related arteriole base brain parenchyma brain tissue capillary bed cell type cerebral blood volume cerebral microvasculature clinically relevant cognitive function density expectation gain of function mutation in vivo in vivo imaging innovation insight loss of function mutation mouse model novel parenchymal arterioles particle pressure receptor response spatiotemporal vascular contributions venule white matter

项目摘要

In response to the FOA, PAR-22-026, we propose an integrated and technologically/conceptually innovative approach to advance our mechanistic understanding of how dysfunction of small brain vessels can have long-term impacts on the brain parenchyma and cause cognitive impairment. Cerebral small vessel disease (cSVD) accounts for up to 25% of ischemic strokes and more than 90% of spontaneous intracerebral hemorrhages (ICHs), and as such is a major driver of dementia. Recent studies have shown that there are at least four types of mural cells defining four major microvascular zones: smooth muscle cells (SMCs) on arterioles, contractile pericytes (PCs) on the post-arteriole region of the capillary bed (i.e., transition zone), non-contractile PCs on distal capillaries and venular PCs on venules. Loss of arteriolar SMCs in human post-mortem brains is a feature shared by both multifactorial and inherited cSVD, whether associated with ischemic strokes or ICHs. We have provided compelling evidence that loss of SMCs on arterioles coupled with enhanced function of contractile PCs on the transition zone mutually reinforce each other to cause ICHs, and recently discovered that arteriolar SMCs and contractile PCs in the transition zone are lost early in the brain and retina of clinically relevant mouse models of ischemic cSVDs with gain- or loss-of-function mutations in the NOTCH3 receptor. On the basis of these and other observations, we propose that loss of SMCs specifically in brain arterioles is a common factor underlying the development of cSVDs and that changes in the properties/density of contractile PCs in the post-arteriole transition zone modify disease presentation. To test this, we will explore the causal relationship between the loss of SMCs/PCs and cSVD- related brain pathologies and cognitive symptoms (Aim 1) and determine how loss of SMCs/contractile PCs compromises integrative vascular functions (Aim 2). To this end, we will employ existing and novel mouse models with conditional inactivation of Notch3 in specific mural cell populations and deploy a powerful array of new techniques, including 1) a novel coordinate-based object analysis methodology capable of simultaneously quantifying all imageable parameters, including small vessel pathology, in massive 4D (3D over time) imaging datasets from high-resolution sections of the entire brain; 2) a novel pressurized retina preparation in conjunction with labeled red blood cells and microspheres for quantitatively assessing the impact of small vessel pathology on intravascular pressure and flow across different microvascular segments; and 3) ultrafast functional ultrasound imaging, an emerging technology that can non-invasively sample cerebral blood volume changes in vivo in a complete coronal section of a mouse brain with a high spatiotemporal resolution, for elucidating how small brain vessel pathologies affect cerebral blood flow regulation in deep parts of the brain. We expect that the proposed studies will contribute to a better understanding of the mechanistic basis of deep brain lesions and cognitive impairment in cSVDs and establish arteriolar SMCs and contractile PCs as critical new targets.

为了响应 FOA，PAR-22-026，我们提出了一种综合的、技术/概念创新的方法来增进我们对小脑血管功能障碍如何对大脑产生长期影响的机制理解实质并导致认知障碍。脑小血管病 (cSVD) 占缺血性心脏病的 25% 中风和超过 90% 的自发性脑出血 (ICH)，因此是痴呆症的主要驱动因素。最近的研究表明，至少有四种类型的壁细胞定义了四个主要的微血管区域：小动脉上的平滑肌细胞 (SMC)、毛细血管床小动脉后区域的收缩周细胞 (PC)（即，过渡区）、远端毛细血管上的非收缩性 PC 和小静脉上的小静脉 PC。人类小动脉平滑肌细胞的损失死后大脑是多因素和遗传性 SVD 共有的一个特征，无论是否与缺血有关中风或脑出血。我们提供了令人信服的证据，证明小动脉 SMC 的丢失与功能的增强相结合过渡区的收缩 PC 相互增强导致 ICH，最近发现过渡区的小动脉 SMC 和收缩性 PC 在临床相关小鼠的大脑和视网膜中早期丢失 NOTCH3 受体功能获得或丧失突变的缺血性 SVD 模型。在此基础上和根据其他观察结果，我们认为 SMC 的丢失（特别是脑小动脉中的 SMC 丢失）是导致该疾病的一个常见因素 CSVD 的发展以及小动脉后过渡区收缩性 PC 的特性/密度的变化修改疾病表现。为了测试这一点，我们将探讨 SMC/PC 丢失与 cSVD 之间的因果关系相关的大脑病理学和认知症状（目标 1）并确定 SMC/收缩性 PC 的损失如何影响综合血管功能（目标 2）。为此，我们将采用现有的和新颖的小鼠模型，并有条件使特定壁细胞群中的 Notch3 失活并部署一系列强大的新技术，包括 1) 新颖的基于坐标的对象分析方法能够同时量化所有可成像参数，包括小血管病理学，来自整个血管高分辨率切片的大规模 4D（随时间变化的 3D）成像数据集脑; 2) 一种新型加压视网膜制剂，与标记的红细胞和微球相结合，用于定量评估小血管病理学对不同血管内压力和血流的影响微血管段； 3）超快功能超声成像，这是一种新兴技术，可以非侵入性地在具有高时空变化的小鼠大脑的完整冠状切片中对体内脑血容量变化进行采样分辨率，用于阐明小脑血管病变如何影响大脑深部的脑血流调节脑。我们期望所提出的研究将有助于更好地理解深层机制的基础 CSVD 中的脑损伤和认知障碍，并将小动脉 SMC 和收缩性 PC 作为重要的新目标。