The Effect of Blood Flow Changes in Brain Microvasculature on Pericyte-Endothelial Cell Interaction

脑微血管血流变化对周细胞-内皮细胞相互作用的影响

• 批准号: 10680128
• 负责人: Hanaa Abdelazim
• 金额: $ 4.23万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2025-06-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680128
• 关键词: Ablation; Acute; Address; Adjuvant; Adult; Affect; Age; Antibodies; Automobile Driving; Binding; Biological Assay; Biomechanics; Biophysics; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; CD31 Antigens; Capillary Permeability; Cause of Death; Cell Communication; Cell physiology; Cells; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular system; Coagulation Process; Cues; Data; Development; Disease; Economic Burden; Effectiveness; Embryonic Development; Endothelial Cells; Extracellular Matrix; Face; Gene Expression; Glucose; Goals; Health; Hemorrhage; Homeostasis; Human; Hypoxia; ITGA5 gene; Image; Impairment; Incubated; Individual; Inflammation; Inflammatory; Inflammatory Response; Injections; Integrin Inhibition; Intercellular Junctions; Interleukin-1 beta; Ischemic Stroke; Knowledge; Lasers; Legal patent; Lentivirus; Life; Link; Measures; Mechanics; Mediating; Metabolic; Microcirculation; Modeling; Molecular; Molecular Analysis; Morphology; Mus; Organ; Patient-Focused Outcomes; Patients; Perfusion; Pericytes; Phase; Physiology; Population; Preparation; Process; Protein Biosynthesis; Proteins; Recovery; Reperfusion Therapy; Reporter; Risk; Scanning Electron Microscopy; Signal Transduction; Signaling Protein; Slice; Small Interfering RNA; Societies; Stroke; Technology; Testing; Thrombectomy; Thrombus; Time; Tissues; Translating; United States; Up-Regulation; Vascular System; Vitronectin; acute stroke; blood-brain barrier function; brain endothelial cell; cadherin 5; cerebral microvasculature; cerebrovascular; clinically significant; confocal imaging; design; disability; hemodynamics; improved; improved outcome; in vivo; in vivo Model; inhibitor; laboratory experience; long term recovery; mechanical signal; next generation; novel; novel therapeutics; overexpression; particle; pharmacologic; postnatal; prevent; public health relevance; receptor; response; stroke patient; stroke therapy; thrombolysis; tool; vector

PROJECT SUMMARY Stroke is one of the most common causes of death and disability in the United States and worldwide. The vascular system is meticulously regulated throughout life to adapt to changes in metabolic demand and blood flow under widely variable conditions. Many ischemic stroke patients however fail to fully recover following an acute attack. This impaired recovery is related in part to the limited return of perfusion within the brain microcirculation, even after restoring the patency of occluded vessels – a scenario referred to as the “no-reflow” phenomenon. Blood circulating within the vascular system exerts different types of forces on the surrounding vessels. These forces are sensed and interpreted by the vascular cells to guide their development during embryogenesis and regulate remodeling during postnatal and adult life. It has been also suggested in recent years that there are signals downstream of mechanical changes that are exchanged between vascular cells. Specifically, pericytes and endothelial cells integrate these cues to dynamically regulate blood vessel physiology, capillary permeability, and changes in microvascular tone in health and in disease. Despite recent advances in our knowledge of flow-mediated biomechanical inputs, the underlying molecular processes and their link to hemodynamic forces in vivo are still emerging, in part due to limitations in the tools and models to measure these forces. To help fill this gap in knowledge, the proposed study aims to investigate the impact of abrupt changes in blood flow on two components of the blood-brain barrier -- pericytes and endothelial cells -- and their interaction in mature brain vessels under static conditions following the loss of flow. We will utilize both ex vivo and in vivo models to establish the mechanistic interactions underlying how pericytes and endothelial cells process, interpret, and organize various mechanical signals. Additionally, we will look at corresponding changes in the surrounding extracellular matrix that might accompany this cellular interplay, specifically interactions between endothelial cell integrin α5 and pericyte-derived vitronectin within the capillary wall. Our preliminary data suggests a two-phase response over time following an acute shift towards static conditions. We propose that an early stage marked by a rapid inflammatory response, involving elevated interleukin-1beta expression, is overlaid by a hypoxia-driven response in a subsequent phase, both contributing to cerebrovascular instability and an increased risk for hemorrhagic conversion of ischemic stroke patients after re-establishing cerebral blood flow. Identifying the key mechanistic determinants responsible for blood vessel destabilization in the brain during the hyper-acute phase of stroke will provide targetable signals that could be clinically significant in advancing stroke therapies.

项目摘要 中风是美国和全球最常见的死亡和残疾原因之一。 血管系统在整个生命中都经过精心调节，以适应代谢需求和血液的变化 在可变条件下流动。但是，许多缺血性中风患者在 急性攻击。这种恢复受损的恢复部分与大脑内部灌注的有限回报有关 微循环，即使恢复了封闭船的通畅性 - 这种情况称为“无流量” 现象。血管系统中的血液循环会在周围施加不同类型的力 船只。这些力是由血管细胞感知和解释的，以指导其发育 胚胎发生并调节产后和成人生活期间的重塑。最近也提出了 在血管细胞之间交换机械变化的几年的几年。 具体而言，周细胞和内皮细胞整合了这些线索，以动态调节血管生理， 毛细血管渗透性以及健康和疾病中微血管张力的变化。尽管最近的进步 我们对流动介导的生物力学输入的了解，潜在的分子过程及其与 体内的血液动力学仍在出现，部分原因是工具和模型的局限性 力量。为了帮助填补知识中的这一空白，拟议的研究旨在调查突然变化的影响 在血脑屏障的两个成分上的血液流动 - 周细胞和内皮细胞 - 及其相互作用 在静态条件下流失后，在成熟的脑血管中。我们将同时使用ex vivo和invivo 建立周细胞和内皮细胞过程的基础机械相互作用的模型， 解释并组织各种机械信号。此外，我们将研究 周围的细胞外基质可能适应这种细胞相互作用，特别是在 毛细管壁内的内皮细胞整联蛋白α5和周细胞衍生的玻璃蛋白。我们的初步数据建议 急性向静态条件转移后，随着时间的流逝，两相响应。我们提出了早期 以快速的炎症反应（涉及白介素1Beta表达升高）标记的阶段被覆盖 在随后的阶段中，低氧驱动的反应既导致脑血管不稳定性，又有原因 重新建立脑血流后，缺血性中风患者出血性转化的风险增加。 识别负责血管在大脑中不稳定的关键机械决定因素 超急性阶段的中风将提供可定位的信号，这些信号可能在临床上具有前进的中风意义 疗法。