The impact of blood pressure variability on neurovascular function

血管内压驱动灌流，这是最佳神经功能的关键。高血压 然而，高血压是认知能力下降的一个危险因素。新出现的证据表明血液增加 高血压发生前的压力变异性(IBPV)是血管认知的有力预测指标 损伤和痴呆症。IBPV介导认知功能下降的机制尚不清楚，是 这一小说提案的主题。脑小动脉的肌源性反应保护大脑免受血液的伤害 可能导致高灌注度或低灌注度的压力波动。机械传感机制在生物医学中是必不可少的 这一过程，但慢性血压升高的影响在神经血管单位的水平上并没有 已经被描述过了。例如，机械敏感的钙离子渗透性阳离子通道表达在 内皮细胞和星形胶质细胞。我们令人兴奋的初步数据表明，血管内压的增加 在高血压增强的过程中，星形胶质细胞的钙离子显著增加。星形胶质细胞钙离子 神经退行性疾病中经常观察到调节失调，这表明它可能是细胞过程的基础。 这会导致体内平衡功能的丧失，并转变为反应性星形胶质细胞。因为反常的血液 血压波动是高血压的早期预测指标，我们将探索其细胞机制 动脉血压的间歇性升高会导致认知能力下降。具体地说，我们将测试中央 慢性IBPV放大机械驱动的NVU钙升高，从而损害星形胶质细胞的假说 动态平衡，降低血液灌注量，导致认知能力下降。研究将在一种新的小鼠身上进行 脉冲性血管紧张素II输注联合血管紧张素转换酶诱导慢性血压变异性增高模型的建立 清醒小鼠的连续血压测量。AIMS 1-3将检验以下假设：1) IBPV损害血管功能，导致脑低灌注量；2)IBPV增加增强肌源性- 诱导星形胶质细胞钙离子升高，并使星形胶质细胞向炎症/反应表型转变；以及3) IBPV损害了感觉诱发的脑血流增加，导致神经元功能障碍。 使用体内和体外方法，我们将把宏观心血管变量与微观细胞联系起来 神经血管单位的事件并评估IBPV如何进行性损害血管、神经胶质细胞和神经元 功能。纵向方法将确定血压波动和 星形胶质细胞、内皮细胞和神经元中异常的钙动态。药理学、分子和遗传学 工具将被用来识别神经血管单位功能丧失的潜在细胞通路。 这一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， 介绍一种新的小鼠模型，以研究IBPV对脑(和多器官)功能的影响，并鉴定 压力导致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。

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.