Forebrain Mechanisms of Neurovascular Dysfunction in Hypertension
高血压神经血管功能障碍的前脑机制
基本信息
- 批准号:7760722
- 负责人:
- 金额:$ 35.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-05 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:Angiotensin IIArteriesAttenuatedBlood PressureBlood VesselsBlood flowBrainCephalicCerebrovascular CirculationCerebrumCharacteristicsChronicDementiaDevelopmentDoseElectron MicroscopyEndothelin A ReceptorEndothelin-1EnzymesEssential HypertensionFluid BalanceFoundationsFunctional disorderGene SilencingGeneticGoalsHormonesHypertensionHypothalamic structureImpaired cognitionInfusion proceduresInstructionLightLinkMediatingMessenger RNAModelingMolecularMusN-Methyl-D-Aspartate ReceptorsNADPH OxidaseNeuronal PlasticityOrganOxidative StressPathway interactionsPatientsPhenylephrinePituitary GlandPlasmaPlayPredispositionPreparationPrincipal InvestigatorProductionProsencephalonProteinsReactive Oxygen SpeciesRegulationRelative (related person)RestRoleSignal TransductionSourceStrokeSubfornical OrganSynapsesTestingTimeUp-RegulationVascular blood supplyVascular resistanceVasoconstrictor AgentsVasopressinsattenuationcerebrovascularcopper zinc superoxide dismutaseinhibitor/antagonistinsightnoveloverexpressionparaventricular nucleuspressureprogramsreceptorrelating to nervous systemresearch studyresponse
项目摘要
PROJECT 4 (ladecola): Forebrain Mechanisms of Neurovascular Dysfunction in Hypertension
The brain is a major target of the end-organ damage produced by hypertension, an effect linked to the
disruption of vital cerebrovascular regulatory mechanisms that threatens the cerebral blood supply and
increases the brain's susceptibility to stroke and dementia. The long-term goal of Project 4 is to unravel the
mechanisms by which hypertension exerts its deleterious effects on the brain. Angll plays a key role in the
pathophysiology of hypertension. Systemic administration of Angll at concentrations not sufficient to elevate
arterial pressure induces hypertension if the administration is sustained in time (slow pressor hypertension).
Synaptic adaptations (neuroplasticity) in the subfornical organ (SFO), one of the forebrain circumventricular
organs, and in the paraventricular nucleus of the hypothalamus (PVN) are critical for the development of the
neurohumoral dysfunction underiying the hypertension. These adaptive changes, turned maladaptive, are
triggered by Angll through activation of ATI receptors in the SFO and consequent production of reactive
oxygen species (ROS). The SFO, in turn, activates NMDA receptors in the PVN, which contribute to the
hypertension by increasing sympathetic outflow and releasing hormones, including vasopressin (AVP).
Circulating Angll and AVP increase the vascular expression of endothelin-1 (ET1), a potent vasoconstrictor
that is upregulated in arteries of patients with essential hypertension. Project 4 will test the hypothesis that
slow pressor hvpertension elicits cerebrovascular dvsfunction, which is mediated by the SFO-PVN pathway
through neurohumoral effects on cerebral blood vessels involving Anall, AVP and ET1. Experiments will be
conducted in mice in which cerebrovascular regulation will be studied using cranial window preparations.
Both pharmacological and genetic approaches will be used to achieve the stated goals. We will test the
following hypotheses: (1) Slow pressor Angll administration disrupts key homeostatic responses of the
cerebral circulation, an effect that may precede the development of hypertension; (2) The central signaling
mechanisms of the cerebrovascular dysfunction involve AT1 receptors and ROS production in the SFO, and
NMDA receptors in the PVN; (3) PVN-derived AVP and circulating Angll induce cerebrovascular dysfunction
through upregulation of ET1 in cerebral blood vessels; (4) Angll and ET1 act synergistically to induce
cerebrovascular dysfunction via NADPH-oxidase derived ROS.
RELEVANCE (See instructions):
Hypertension is the leading cause of stroke and vascular cognitive impairment. However, the mechanisms of
these effects are pooriy understood. The proposed studies represent the first exploration of the role of the
SFO-PVN axis in the cerebrovascular dysfunction induced by slow pressor hypertension. The results will
provide novel insights into the fundamental mechanisms by which hypertension alters the cerebral circulation
and may suggest new therapies to protect the brain from the devastating effects of hypertension.
项目4 (ladecola):高血压患者神经血管功能障碍的前脑机制
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Costantino Iadecola其他文献
Costantino Iadecola的其他文献
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{{ truncateString('Costantino Iadecola', 18)}}的其他基金
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High-speed imaging of cortical and white matter microvascular flow in AD/ADRD models
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10523289 - 财政年份:2022
- 资助金额:
$ 35.26万 - 项目类别:
ApoE4, Neurovascular Injury and Cognitive Impairment
ApoE4、神经血管损伤和认知障碍
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10593979 - 财政年份:2022
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ApoE4 and mechanisms of diffuse white matter injury
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$ 35.26万 - 项目类别:
ApoE4 and mechanisms of diffuse white matter injury
ApoE4 与弥漫性白质损伤的机制
- 批准号:
9355719 - 财政年份:2016
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ApoE4 and mechanisms of diffuse white matter injury
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Dietary sodium, neurovascular dysfunction and cerebrovascular risk
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10298081 - 财政年份:2015
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