Kim Ki Jung, Iddings Jennifer A, Stern Javier E, Blanco Víctor M, Croom Deborah, Kirov Sergei A, Filosa Jessica A
Georgia Regents University, Augusta, Georgia 30912, and.
University of Cincinnati, Cincinnati, Ohio 45221.
J Neurosci. 2015 May 27;35(21):8245-57. doi: 10.1523/JNEUROSCI.4486-14.2015.
Basal and activity-dependent cerebral blood flow changes are coordinated by the action of critical processes, including cerebral autoregulation, endothelial-mediated signaling, and neurovascular coupling. The goal of our study was to determine whether astrocytes contribute to the regulation of parenchymal arteriole (PA) tone in response to hemodynamic stimuli (pressure/flow). Cortical PA vascular responses and astrocytic Ca(2+) dynamics were measured using an in vitro rat/mouse brain slice model of perfused/pressurized PAs; studies were supplemented with in vivo astrocytic Ca(2+) imaging. In vitro, astrocytes responded to PA flow/pressure increases with an increase in intracellular Ca(2+). Astrocytic Ca(2+) responses were corroborated in vivo, where acute systemic phenylephrine-induced increases in blood pressure evoked a significant increase in astrocytic Ca(2+). In vitro, flow/pressure-evoked vasoconstriction was blunted when the astrocytic syncytium was loaded with BAPTA (chelating intracellular Ca(2+)) and enhanced when high Ca(2+) or ATP were introduced to the astrocytic syncytium. Bath application of either the TRPV4 channel blocker HC067047 or purinergic receptor antagonist suramin blunted flow/pressure-evoked vasoconstriction, whereas K(+) and 20-HETE signaling blockade showed no effect. Importantly, we found TRPV4 channel expression to be restricted to astrocytes and not the endothelium of PA. We present evidence for a novel role of astrocytes in PA flow/pressure-evoked vasoconstriction. Our data suggest that astrocytic TRPV4 channels are key molecular sensors of hemodynamic stimuli and that a purinergic, glial-derived signal contributes to flow/pressure-induced adjustments in PA tone. Together our results support bidirectional signaling within the neurovascular unit and astrocytes as key modulators of PA tone.
基础和活动依赖性脑血流变化由关键过程协调，包括脑自动调节、内皮介导的信号传导和神经血管耦合。我们研究的目的是确定星形胶质细胞是否有助于响应血流动力学刺激（压力/流量）来调节实质小动脉（PA）张力。使用灌注/加压PA的体外大鼠/小鼠脑片模型测量皮质PA血管反应和星形胶质细胞Ca(2+)动力学；研究通过体内星形胶质细胞Ca(2+)成像进行补充。在体外，星形胶质细胞对PA流量/压力增加的反应是细胞内Ca(2+)增加。星形胶质细胞Ca(2+)反应在体内得到证实，其中急性全身去氧肾上腺素诱导的血压升高引起星形胶质细胞Ca(2+)显著增加。在体外，当星形胶质细胞合体负载BAPTA（螯合细胞内Ca(2+)）时，流量/压力诱发的血管收缩减弱，而当向星形胶质细胞合体引入高Ca(2+)或ATP时增强。浴用TRPV4通道阻滞剂HC067047或嘌呤能受体拮抗剂苏拉明可减弱流量/压力诱发的血管收缩，而K(+)和20-HETE信号传导阻断则无作用。重要的是，我们发现TRPV4通道表达仅限于星形胶质细胞，而非PA的内皮细胞。我们提供了星形胶质细胞在PA流量/压力诱发的血管收缩中具有新作用的证据。我们的数据表明，星形胶质细胞TRPV4通道是血流动力学刺激的关键分子传感器，并且嘌呤能、胶质细胞衍生的信号有助于流量/压力诱导的PA张力调节。我们的结果共同支持神经血管单元内的双向信号传导以及星形胶质细胞作为PA张力的关键调节因子。
