Astrocytes regulation of vascular tone: role in hypertension

描述(申请人提供)：高血压损害认知功能，是中风、阿尔茨海默病和血管性痴呆症的主要危险因素。然而，心血管疾病和神经血管病变之间联系的潜在机制尚未阐明。采用多学科的方法，包括对GFAP-GCamP3小鼠的体外和体内研究，我们提出了一个中心假设，即星形胶质细胞通过激活TRPV4通道和依赖钙离子产生20-HETE来增加血管张力，从而积极参与脑自我调节。此外，我们假设高血压患者星形胶质细胞来源的20-HETE的产生增加会导致PA的肌源性收缩增强。这一假说预测，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，我们将验证星形胶质细胞通过机械敏感的TRPV4通道感知血流动力学刺激并将其转换为特定的钙反应模式的假设。目的2将探讨血流动力学诱导的星形胶质细胞钙反应是否有助于血管收缩因子20-HETE的产生，从而支持PA血管张力的增加。最后，在目标3中，使用GPAP-GCamP3小鼠的Ang II高血压模型，我们将检验这一假设，即压力诱导的星形胶质细胞钙离子增加，通过TRPV4通道激活，增强20-HETE介导的高血压患者PA的收缩。我们期待这项研究的发现，通过阐明与心血管疾病相关的神经血管病理的新的非血管治疗靶点来推动这一领域的发展。本研究将：1)确定星形胶质细胞在控制血管张力和脑自身调节中的新功能；2)确定肌源性PA收缩的潜在细胞靶点；3)确定慢性高血压对星形胶质细胞介导的血管张力改变的影响。

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.