Capillary control of cerebral blood flow, and its disruption in small vessel disease

毛细血管控制脑血流及其在小血管疾病中的破坏

基本信息

批准号：
9291583
负责人：
Fabrice Dabertrand
金额：
$ 40.08万
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：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9291583
关键词：
Anatomy Animal Model Animals Blood capillaries Blood flow Brain Brain Diseases CADASIL Calcium Signaling Capillary Endothelial Cell Cells Cerebral small vessel disease Cerebrovascular Circulation Cerebrum Characteristics Communication Complement Complex Comprehension Computer Simulation DTR gene Data Defect Depressed mood Dinoprostone Disintegrins Down-Regulation Endothelial Cells Endothelium Energy Supply Epidermal Growth Factor Receptor Equilibrium Exhibits Extracellular Matrix Extracellular Matrix Proteins Foundations G-Protein-Coupled Receptors Genetic Goals Hyperemia Impairment Inherited Inositol Laser Scanning Microscopy Ligands Matrix Metalloproteinase Inhibitor Measurement Mediating Mediator of activation protein Metalloproteases Microcirculation Microvascular Dysfunction Modality Mus Muscle Cells Neurons Nutrient Pathogenicity Pathway interactions Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Physiological Positioning Attribute Potassium Channel Preparation Prostaglandins Receptor Signaling Regulation Reporting Role Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stroke TIMP3 gene Testing Tissues Translating Travel Up-Regulation Vanilloid Vascular Cognitive Impairment Vascular blood supply Vasodilation War Work arteriole base capillary cerebral capillary cerebral hemodynamics cerebrovascular clinically relevant density extracellular feeding in vivo insight knockout animal lens mouse model neurovascular coupling novel overexpression parenchymal arterioles pressure receptor relating to nervous system response two-photon voltage

项目摘要

The survival of neurons in the brain depends on an uninterrupted, dynamically regulated supply of blood- borne nutrients, which are delivered through a dense capillary network. Despite extensive study, the mechanisms underlying the functional linkage between neuronal demand and vascular supply, termed neurovascular coupling (NVC), remains poorly understood. Anatomically, intracerebral (parenchymal) arterioles form bottlenecks that precisely control cerebral hemodynamics, and capillary endothelial cells are ideally positioned to detect neuronal activity. We propose that prostaglandin E2 (PGE2), a suggested NVC mediator, acts at the level of capillaries to initiate a Ca2+ wave that travels along endothelial cells to reach the upstream arteriole, where it triggers vasodilation through endothelium-dependent hyperpolarization. Our extensive preliminary data also describe a capillary signaling complex between the epidermal growth factor receptor (EGFR) and transient receptor potential vanilloid 3 (TRPV3) channels that is involved in generating this PGE2-induce retrograde Ca2+ signal. Using a well-established genetic mouse model of CADASIL, a hereditary form of small vessel disease, we further propose that pathogenic mechanisms that result in EGFR pathway inhibition in smooth muscle also depress EGFR/TRPV3 signaling complex in capillaries, resulting in impaired NVC. To test these ideas, we engage a wide variety of novel, state-of-the-art experimental approaches using intact animals, native tissue and freshly isolated cells, complemented by sophisticated computational modeling. Aim 1 will explore how capillary PGE2 and TRPV3 signaling generates retrograde Ca signals to 2+ cause upstream arteriolar dilation, taking advantage of our newly developed pressurized arteriole-capillary ex vivo preparation. Using extracellular matrix disruptions characteristic of CADASIL as a framework, Aim 2 will provide the first insights into the mechanisms by which TRPV3 channels and evoked upstream dilation are regulated by EGFR and its upstream regulators TIMP3, a matrix metalloproteinase inhibitor, and ADAM17, a metalloproteinase that mediates shedding of the EGFR ligand, HB-EGF. Building on our previous report that CADASIL causes voltage-gated K (KV) channel upregulation in arteriolar myocytes, Aim 3 will explore the + hypothesis that increased KV current density limits arteriolar conducted dilation, and thus NVC, initiated by capillary PGE2/TRPV3 signaling in CADASIL. The proposed work has the potential to revolutionize our understanding of communication within the brain microcirculation, and as such should provide the foundation for understanding small vessel diseases of the brain.

神经元在大脑中的存活取决于不间断的，动态调节的血液供应通过密集的毛细血管网络传递的繁殖营养素。尽管进行了广泛的研究，但神经元需求与血管供应之间功能连接的基础机制，称为神经血管耦合（NVC）仍然了解不足。解剖学，脑内（实质）小动脉形成精确控制脑血液动力学的瓶颈，毛细血管内皮细胞是理想位置可检测神经元活性。我们建议前列腺素E2（PGE2），建议的NVC 调解器，作用于毛细管的水平，以启动沿着内皮细胞传播的Ca2+波上游动脉，它通过内皮依赖性超极化触发血管舒张。我们的广泛的初步数据还描述了表皮生长因子之间的毛细管信号传导复合物受体（EGFR）和瞬态受体电势香草素3（TRPV3）通道，与生成有关该PGE2引诱逆行Ca2+信号。使用公认的CADASIL遗传小鼠模型A 小血管疾病的遗传形式，我们进一步提出导致EGFR的致病机制平滑肌抑制途径还会抑制毛细血管中的EGFR/TRPV3信号传导复合物，从而导致 NVC受损。为了测试这些想法，我们参与了各种各样的新颖，最先进的实验方法使用完整的动物，天然组织和新鲜分离的细胞，并得到复杂的计算造型。 AIM 1将探讨毛细管PGE2和TRPV3信号如何生成逆行CA信号 2+ 引起上游小动脉扩张，利用我们新开发的加压小动脉毛细管EX 体内准备。使用Cadasil作为框架的细胞外基质破坏特征，AIM 2将提供有关TRPV3通道和唤起上游扩张的机制的第一个见解由EGFR及其上游调节剂Timp3（基质金属蛋白酶抑制剂）和ADAM17（A）调节金属蛋白酶介导EGFR配体HB-EGF的脱落。以我们先前的报告为基础 CADASIL导致电压门控k（KV）通道上调在小动脉肌细胞中，AIM 3将探索 + 假设增加KV电流密度限制了动脉扩张，因此NVC，由毛细管PGE2/TRPV3信号传导。拟议的工作有可能改变我们的了解大脑微循环中的沟通，因此应为基础提供基础了解大脑的小血管疾病。