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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结