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The impact of blood pressure variability on neurovascular function

血压变异性对神经血管功能的影响

基本信息

批准号：
10745027
负责人：
JESSICA A FILOSA
金额：
$ 64.3万
依托单位：
AUGUSTA UNIVERSITY
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：
2023-08-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745027
关键词：
Acute Address Angiotensin II Astrocytes Blood Pressure Blood Vessels Brain Calcium Cardiovascular system Cations Cell physiology Cerebrovascular Circulation Cerebrum Chronic Conscious Coupled Data Dementia Development Diameter Diastolic blood pressure Endothelial Cells Erythrocytes Event Functional disorder Genetic Gliosis Heart Rate Homeostasis Hypertension Image Immunohistochemistry Impaired cognition Impairment Implant Inflammation Inflammatory Infusion Pumps Infusion procedures Lasers Link Measurement Measures Mediating Microscopic Modeling Molecular Molecular Target Monitor Mus Neurodegenerative Disorders Neuronal Dysfunction Neurons Nutrient Organ Oxygen Pathway interactions Perfusion Permeability Phenotype Process Reflex action Risk Factors Saline Sensory Slice Systemic blood pressure Technology Telemetry Testing Viral arteriole blood pressure elevation blood pressure variability cellular targeting cerebral hypoperfusion cognitive function constriction early onset hypoperfusion in vivo innovation loss of function mouse model neurovascular neurovascular coupling neurovascular unit novel parenchymal arterioles pharmacologic pressure response subcutaneous tool transcriptome sequencing two photon microscopy two-photon vascular cognitive impairment and dementia

项目摘要

Intravascular pressure drives perfusion, which is critical for optimal neuronal function. High blood pressure (hypertension), however, is a risk factor for cognitive decline. Emerging evidence identifies increased blood pressure variability (IBPV), before the development of hypertension, as a strong predictor for vascular cognitive impairment and dementia. The mechanism whereby IBPV mediates cognitive decline is unknown and is the subject of this novel proposal. The myogenic response of cerebral arterioles protects the brain from blood pressure fluctuations that could cause hyper- or hypoperfusion. Mechanosensory mechanisms are essential in this process, but the impact of chronic blood pressure elevations at the level of the neurovascular unit has not been previously described. For example, mechanosensitive Ca2+-permeable cation channels are expressed on endothelial cells and astrocytes. Our exciting preliminary data demonstrate that increased intravascular pressure significantly increased astrocyte Ca2+ in a a process that is enhanced in hypertension. Astrocyte Ca2+ dysregulation is often observed in neurodegenerative diseases suggesting it may underlie cellular processes that contribute to the loss of homeostatic function and transition into reactive astrocytes. Because aberrant blood pressure fluctuations are an early predictor of hypertension, we will explore the cellular mechanisms by which intermittent increases in arterial pressure contribute to cognitive decline. Specifically, we will test the central hypothesis that chronic IBPV amplifies mechano-driven Ca2+ increases at the NVU, which impairs astrocyte homeostasis, decreases perfusion, and causes cognitive decline. Studies will be conducted in a novel murine model of chronic increased blood pressure variability induced by pulsatile angiotensin II infusion coupled with continuous blood pressure measurement in conscious mice. Aims 1-3 will test the following hypotheses: 1) that IBPV impairs vascular function and causes cerebral hypoperfusion; 2) that increased IBPV enhances myogenic- induced increases in astrocyte Ca2+and shifts astrocytes toward a pro-inflammatory/reactive phenotype; and 3) that IBPV compromises sensory-evoked increases in cerebral blood flow, contributing to neuronal dysfunction. Using in vivo and ex vivo approaches, we will link macroscopic cardiovascular variables to microscopic cellular events at the neurovascular unit and assess how IBPV progressively impairs vascular, glial and neuronal function. A longitudinal approach will determine the relationship between blood pressure fluctuations and aberrant Ca2+ dynamics in astrocytes, endothelial cells and neurons. Pharmacological, molecular, and genetic tools will be used to identify the cellular pathways underlying the loss of function at the neurovascular unit. Findings from this innovative application will establish IBPV as a key driver and predictor of cognitive decline, introduce a novel murine model to investigate the impact of IBPV on brain (and multi-organ) function, and identify cellular and molecular targets of pressure-induced vascular and astrocyte dysfunction leading to compromised cerebral perfusion and ultimately, neuronal dysfunction.

血管内压力驱动灌注，这对优化神经元功能至关重要。高血压