Functional Tuning of Intrinsic Endothelial Ca2+ Dynamics in Swine Coronary Arteries.
Functional Tuning of Intrinsic Endothelial Ca2+ Dynamics in Swine Coronary Arteries.
复制标题
DOI：
10.1161/circresaha.115.308141
复制
发表时间：
2016-04-01
影响因子：
20.1
通讯作者：
Taylor MS
中科院分区：
文献类型：
--
作者：
Francis M;Waldrup JR;Qian X;Solodushko V;Meriwether J;Taylor MS
最近来自肠系膜和脑床的数据显示，沿着血管内膜发生空间受限的 Ca2+ 瞬变，控制效应器募集和血管舒张。虽然 Ca2+ 对冠状动脉内皮功能至关重要，但人们对冠状动脉内皮功能性 Ca2+ 信号的空间和时间调节知之甚少。我们的目的是确定 Ca2+ 动态的离散空间和时间分布是否是猪冠状动脉 (SCA) 内皮依赖性松弛的基础。使用共焦成像、定制自动图像分析和肌动描记术，我们表明 SCA 内皮产生离散的基础 Ca2+ 动力学，包括孤立的瞬态和全细胞传播波。这些事件可通过消耗内部储存或抑制肌醇 1,4,5-三磷酸受体 (IP3R) 来抑制，但不能通过抑制兰尼碱受体或去除细胞外 Ca2+ 来抑制。在血管环中，抑制特定的 Ca2+ 依赖性内皮效应器，即小电导 K+ 通道和中电导 K+ 通道 (KCa3.1、KCa2.3) 和内皮一氧化氮合酶 (eNOS)，会产生附加音调，该音调会因内部储存耗尽或 IP3R 阻断而减弱。用 P 物质刺激内皮 IP3 依赖性信号传导会导致动态 Ca2+ 信号参数（活性位点、事件频率、幅度、持续时间和空间分布）发生特殊变化。总体而言，P 物质诱导的血管舒张与全视野内皮 Ca2+ 测量结果的对应性较差，但与 Ca2+ 动力学（动态参数的线性平移复合）的浓度依赖性变化精确对应。我们的研究结果表明，SCA 张力的内皮依赖性控制是由固有内皮 Ca2+ 动态的空间和时间滴定决定的，而这些动态并不由组织水平平均 Ca2+ 变化表示。
Recent data from mesenteric and cerebral beds have revealed spatially restricted Ca2+ transients occurring along the vascular intima that control effector recruitment and vasodilation. While Ca2+ is pivotal for coronary artery endothelial function, spatial and temporal regulation of functional Ca2+ signals in the coronary endothelium is poorly understood. We aimed to determine whether a discrete spatial and temporal profile of Ca2+ dynamics underlies endothelium-dependent relaxation of swine coronary arteries (SCA). Using confocal imaging, custom automated image analysis, and myography we show that the SCA endothelium generates discrete basal Ca2+ dynamics including isolated transients and whole-cell propagating waves. These events are suppressed by depletion of internal stores or inhibition of inositol 1,4,5-trisphosphate receptors (IP3R), but not by inhibition of ryanodine receptors or removal of extracellular Ca2+. In vessel rings, inhibition of specific Ca2+-dependent endothelial effectors, namely small and intermediate conductance K+ channels (KCa3.1, KCa2.3) and endothelial nitric oxide synthase (eNOS), produces additive tone, which is blunted by internal store depletion or IP3R blockade. Stimulation of endothelial IP3-dependent signaling with substance P causes idiosyncratic changes in dynamic Ca2+ signal parameters (active sites, event frequency, amplitude, duration, and spatial spread). Overall, substance P-induced vasorelaxation corresponded poorly with whole-field endothelial Ca2+ measurements, but corresponded precisely with the concentration-dependent change in Ca2+ dynamics (linearly translated composite of dynamic parameters). Our findings show that endothelium-dependent control of SCA tone is determined by spatial and temporal titration of inherent endothelial Ca2+ dynamics that are not represented by tissue-level averaged Ca2+ changes.