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:
- 金额:$ 64.3万
- 依托单位:
- 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:
- 关键词:AcuteAddressAngiotensin IIAstrocytesBlood PressureBlood VesselsBrainCalciumCardiovascular systemCationsCell physiologyCerebrovascular CirculationCerebrumChronicConsciousCoupledDataDementiaDevelopmentDiameterDiastolic blood pressureEndothelial CellsErythrocytesEventFunctional disorderGeneticGliosisHeart RateHomeostasisHypertensionImageImmunohistochemistryImpaired cognitionImpairmentImplantInflammationInflammatoryInfusion PumpsInfusion proceduresLasersLinkMeasurementMeasuresMediatingMicroscopicModelingMolecularMolecular TargetMonitorMusNeurodegenerative DisordersNeuronal DysfunctionNeuronsNutrientOrganOxygenPathway interactionsPerfusionPermeabilityPhenotypeProcessReflex actionRisk FactorsSalineSensorySliceSystemic blood pressureTechnologyTelemetryTestingViralarterioleblood pressure elevationblood pressure variabilitycellular targetingcerebral hypoperfusioncognitive functionconstrictionearly onsethypoperfusionin vivoinnovationloss of functionmouse modelneurovascularneurovascular couplingneurovascular unitnovelparenchymal arteriolespharmacologicpressureresponsesubcutaneoustooltranscriptome sequencingtwo photon microscopytwo-photonvascular 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JESSICA A FILOSA其他文献
JESSICA A FILOSA的其他文献
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{{ truncateString('JESSICA A FILOSA', 18)}}的其他基金
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:
10419670 - 财政年份:2021
- 资助金额:
$ 64.3万 - 项目类别:
Inverse neurovascular coupling in the hypothalamus and its role in positive feedback regulation of Vasopressin neurons in health and disease
下丘脑的逆神经血管耦合及其在健康和疾病中加压素神经元正反馈调节中的作用
- 批准号:
10391639 - 财政年份:2021
- 资助金额:
$ 64.3万 - 项目类别:
Inverse neurovascular coupling in the hypothalamus and its role in positive feedback regulation of Vasopressin neurons in health and disease
下丘脑的逆神经血管耦合及其在健康和疾病中加压素神经元正反馈调节中的作用
- 批准号:
10531928 - 财政年份:2021
- 资助金额:
$ 64.3万 - 项目类别:
Clinically unscreened vasculo-glial-neuronal coupling is critical for physiological brain function
临床上未经筛选的血管-胶质-神经元耦合对于生理脑功能至关重要
- 批准号:
9884817 - 财政年份:2017
- 资助金额:
$ 64.3万 - 项目类别:
Clinically unscreened vasculo-glial-neuronal coupling is critical for physiological brain function
临床上未经筛选的血管-胶质-神经元耦合对于生理脑功能至关重要
- 批准号:
10117289 - 财政年份:2017
- 资助金额:
$ 64.3万 - 项目类别:
Clinically unscreened vasculo-glial-neuronal coupling is critical for physiological brain function
临床上未经筛选的血管-胶质-神经元耦合对于生理脑功能至关重要
- 批准号:
9442869 - 财政年份:2017
- 资助金额:
$ 64.3万 - 项目类别:
Clinically unscreened vasculo-glial-neuronal coupling is critical for physiological brain function
临床上未经筛选的血管-胶质-神经元耦合对于生理脑功能至关重要
- 批准号:
9311373 - 财政年份:2017
- 资助金额:
$ 64.3万 - 项目类别:
Signals and targets underlying mechanisms for neurovascular coupling in the brain
大脑神经血管耦合的信号和目标潜在机制
- 批准号:
7841408 - 财政年份:2009
- 资助金额:
$ 64.3万 - 项目类别:
Signals and targets underlying mechanisms for neurovascular coupling in the brain
大脑神经血管耦合的信号和目标潜在机制
- 批准号:
7806456 - 财政年份:2007
- 资助金额:
$ 64.3万 - 项目类别:
Signals and targets underlying mechanisms for neurovascular coupling in the brain
大脑神经血管耦合的信号和目标潜在机制
- 批准号:
8059688 - 财政年份:2007
- 资助金额:
$ 64.3万 - 项目类别:
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