The impact of blood pressure variability on neurovascular function

血压变异性对神经血管功能的影响

• 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
• 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

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，这对于最佳神经元功能至关重要。高血压 然而，高血压是认知能力下降的危险因素。新出现的证据表明血液增加 血压变异性（IBPV），在高血压发展之前，作为血管认知功能的强有力预测因素 损伤和痴呆。IBPV介导认知能力下降的机制尚不清楚， 这一新提案的主题。大脑小动脉的肌源性反应保护大脑免受血液 压力波动可能导致灌注过多或灌注不足。机械感觉机制是必不可少的， 这一过程，但慢性血压升高的影响，在神经血管单位的水平没有 以前描述过。例如，机械敏感性Ca 2+渗透性阳离子通道表达于 内皮细胞和星形胶质细胞。我们令人兴奋的初步数据表明，血管内压力的增加 在高血压中增强的一个过程中显著增加星形胶质细胞Ca 2+。星形胶质细胞Ca 2 + 在神经退行性疾病中经常观察到调节异常，这表明它可能是细胞过程的基础 导致体内平衡功能丧失并转变为反应性星形胶质细胞。因为异常的血液 压力波动是高血压的早期预测因素，我们将探讨细胞机制， 动脉压的间歇性升高导致认知能力下降。具体来说，我们将测试中央 假设慢性IBPV放大了NVU处机械驱动的Ca 2+增加，这损害了星形胶质细胞 体内平衡，减少灌注，并导致认知能力下降。研究将在一种新的小鼠中进行。 脉动式血管紧张素II输注诱导的慢性血压变异性增加模型， 在清醒小鼠中连续测量血压。目标1-3将检验以下假设：1） IBPV损害血管功能并导致脑灌注不足; 2）IBPV增加可增强肌源性- 诱导星形胶质细胞Ca 2+增加并使星形胶质细胞向促炎/反应性表型转变;和3） IBPV损害感觉诱发的脑血流量增加，导致神经元功能障碍。 使用体内和体外方法，我们将宏观心血管变量与微观细胞 在神经血管单位的事件，并评估如何IBPV进行性损害血管，神经胶质和神经元 功能纵向方法将确定血压波动与 星形胶质细胞、内皮细胞和神经元中异常的Ca 2+动力学。药理学、分子学和遗传学 将使用工具来识别神经血管单元功能丧失的细胞通路。 这项创新应用的发现将使IBPV成为认知能力下降的关键驱动因素和预测因素， 引入一种新的小鼠模型来研究IBPV对脑（和多器官）功能的影响，并鉴定 压力诱导的血管和星形胶质细胞功能障碍的细胞和分子靶点， 脑灌注并最终导致神经元功能障碍。