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.

项目概要 中风是美国和全世界最常见的死亡和残疾原因之一。 血管系统在整个生命过程中都受到精心调节，以适应代谢需求和血液的变化 然而，许多缺血性中风患者在各种情况下都无法完全康复。 这种急性发作的恢复受损部分与脑内灌注恢复有限有关。 即使在闭塞血管恢复通畅后，微循环仍然存在——这种情况被称为“无复流” 血管系统内循环的血液对周围环境施加不同类型的力。 血管细胞感知并解释这些力，以指导其发育。 最近还提出了胚胎发生并调节出生后和成年期间的重塑。 多年来，血管细胞之间交换机械变化的下游信号。 具体来说，周细胞和内皮细胞整合这些线索来动态调节血管生理学， 尽管最近在健康和疾病中取得了进展，但毛细血管通透性以及微血管张力的变化。 我们对流介导的生物力学输入、潜在分子过程及其与 体内血流动力学仍在不断出现，部分原因是测量这些血流动力学的工具和模型的局限性 为了帮助填补这一知识空白，拟议的研究旨在调查突然变化的影响。 血脑屏障的两个组成部分（周细胞和内皮细胞）上的血流及其相互作用 在血流丧失后静态条件下的成熟脑血管中，我们将利用离体和体内两种方法。 建立周细胞和内皮细胞如何处理的机制相互作用的模型， 此外，我们还将研究各种机械信号的相应变化。 周围的细胞外基质可能伴随这种细胞相互作用，特别是之间的相互作用 我们的初步数据表明，毛细血管壁内存在内皮细胞整合素 α5 和周细胞衍生的玻连蛋白。 我们建议尽早向静态条件转变后随时间的两阶段响应。 以快速炎症反应为标志的阶段，涉及白细胞介素-1β表达升高，被 随后阶段的缺氧驱动反应，既导致脑血管不稳定，又导致 重新建立脑血流后缺血性中风患者发生出血性转化的风险增加。 确定导致大脑血管不稳定的关键机制决定因素 中风的超急性期将提供可针对中风进展具有临床意义的目标信号 疗法。