Astrocytes regulation of vascular tone: role in hypertension

星形胶质细胞调节血管张力：在高血压中的作用

基本信息

批准号：
9302508
负责人：
JESSICA A FILOSA
金额：
$ 38万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302508
关键词：
Address Alzheimer&apos s Disease Astrocytes Blood Vessels Blood capillaries Brain Caliber Cardiovascular Diseases Cerebrovascular Circulation Cerebrum Chronic Data Disease Ensure Glial Fibrillary Acidic Protein Health Homeostasis Hydroxyeicosatetraenoic Acids Hypertension Impaired cognition Impairment In Vitro Lead Link Measures Mediating Modeling Molecular Monitor Mus Neurodegenerative Disorders Neurons Pathology Pattern Perfusion Process Production Regulation Resistance Risk Factors Role Signal Transduction Slice Stimulus Stroke System Systemic blood pressure Testing Time Transgenic Organisms Vascular Dementia Vascular Diseases Vasoconstrictor Agents arteriole capillary cellular targeting cerebral artery cerebrovascular cognitive function constriction density experimental study hemodynamics hypoperfusion in vivo interdisciplinary approach neurovascular neurovascular unit novel parenchymal arterioles pressure public health relevance response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Hypertension impairs cognitive function and is a leading risk factor for stroke, Alzheimer's disease and vascular dementia. Yet, the mechanisms underlying the link between cardiovascular diseases and neurovascular pathologies have not been elucidated. Using a multidisciplinary approach which includes in vitro and in vivo studies in GFAP-GCamP3 mice we propose the central hypothesis that astrocytes actively participate in cerebral autoregulation by increasing vascular tone via TRPV4 channel activation and Ca2+-dependent production of 20-HETE. Further, we hypothesize that augmented astrocyte- derived 20-HETE production in hypertension causes enhanced myogenic constriction of PA. This hypothesis predicts that cerebrovascular tone and reactivity are tightly monitored by perivascular astrocytes. In Aim 1 we will test the hypothesis that astrocytes sense and transduce hemodynamic stimuli into specific Ca2+ response patterns via mechanosensitive TRPV4 channels. Aim 2 will address whether hemodynamic-induced astrocytic Ca2+ responses contribute to the production of the vasoconstrictor 20-HETE, supporting increased vascular tone in PA. Finally, in Aim 3 using the ANG II model of hypertension in GPAP- GCamP3 mice we will test the hypothesis that pressure-induced increased astrocytic Ca2+, via TRPV4 channel activation, enhances 20-HETE mediated constriction of PA in hypertension. We anticipate findings from this study to move the field forwards by elucidating a novel non-vascular therapeutic target for neurovascular pathologies associated with cardiovascular diseases. This study will: 1) characterize a novel function of astrocytes in the control of vascular tone and cerebral autoregulation; 2) define the cellular targets underlying myogenic- induced constriction of PA and; 3) define the consequences of chronic hypertension on astrocytic-mediated alterations in vascular tone.

描述（由申请人提供）：高血压会损害认知功能，是中风、阿尔茨海默病和血管性痴呆的主要危险因素。然而，心血管疾病和神经血管病理之间联系的机制尚未阐明。采用多学科方法，包括 GFAP-GCamP3 小鼠的体外和体内研究，我们提出了一个中心假设：星形胶质细胞通过 TRPV4 通道激活和 Ca2+ 依赖性的 20-HETE 产生增加血管张力，从而积极参与大脑自动调节。此外，我们假设高血压中星形胶质细胞衍生的 20-HETE 产量增加会导致 PA 肌源性收缩增强。该假设预测脑血管张力和反应性受到血管周围星形胶质细胞的密切监测。在目标 1 中，我们将测试星形胶质细胞通过机械敏感 TRPV4 通道感知血流动力学刺激并将其转换为特定 Ca2+ 反应模式的假设。目标 2 将解决血流动力学诱导的星形细胞 Ca2+ 反应是否有助于血管收缩剂 20-HETE 的产生，从而支持 PA 中血管张力的增加。最后，在目标 3 中，我们将使用 GPAP-GCamP3 小鼠的 ANG II 高血压模型来测试以下假设：压力诱导的星形胶质细胞 Ca2+ 增加，通过 TRPV4 通道激活，增强高血压中 20-HETE 介导的 PA 收缩。我们预计这项研究的结果将通过阐明与心血管疾病相关的神经血管病理的新型非血管治疗靶点来推动该领域向前发展。这项研究将：1）表征星形胶质细胞在控制血管张力和大脑自动调节方面的新功能； 2) 定义肌源性诱发 PA 收缩的细胞靶标； 3）定义慢性高血压对星形细胞介导的血管张力改变的影响。