Toward a multiscale description of microvascular flow regulation: o(2)-dependent release of ATP from human erythrocytes and the distribution of ATP in capillary networks.
Toward a multiscale description of microvascular flow regulation: o(2)-dependent release of ATP from human erythrocytes and the distribution of ATP in capillary networks.
复制标题
DOI：
10.3389/fphys.2012.00246
复制
发表时间：
2012
影响因子：
4
通讯作者：
Stephenson AH
中科院分区：
文献类型：
--
作者：
Goldman D;Fraser GM;Ellis CG;Sprague RS;Ellsworth ML;Stephenson AH
整合的许多机制，已建议有助于优化O2供应，以满足骨骼肌中的O2需求，需要一个系统生物学的方法，允许量化这些生理过程在很宽的范围内的长度尺度。在这里，我们描述了两个单独的计算模型的基础上，在体内和体外的研究，当纳入一个单一的强大的多尺度模型，将提供信息的作用，红细胞释放的ATP在骨骼肌灌注分布在生理和病理生理条件下。暴露于低O2张力的健康人类红细胞通过一种充分表征的信号通路释放ATP，需要激活G蛋白、GI和腺苷酸环化酶，导致cAMP增加。然后，该cAMP激活PKA，随后激活CFTR，最终通过泛连接蛋白1释放ATP。该途径中的关键控制点是cAMP的水平，其由途径特异性磷酸二酯酶调节。使用与测量的红细胞ATP释放一致的时间常数（~100 ms），我们构建了该途径的动态模型。该模型预测的ATP释放水平与在广泛的血红蛋白O2饱和度（sO2）范围内获得的测量结果一致。该模型进一步预测了在糖尿病前期发现的浓度下胰岛素如何增强PDE 3的活性并降低细胞内cAMP水平，从而导致红细胞中低O2诱导的ATP释放降低。第二个模型，耦合O2和ATP运输毛细血管网络，显示如何血管内ATP和由此产生的传导血管舒张受局部sO2，对流和ATP降解。该模型还预测了胰岛素水平升高导致ATP释放减少的网络水平效应。两者合计，这些模型奠定了基础，研究系统生物学的红细胞衍生的ATP的微血管灌注分布的调节。
Integration of the numerous mechanisms that have been suggested to contribute to optimization of O2 supply to meet O2 need in skeletal muscle requires a systems biology approach which permits quantification of these physiological processes over a wide range of length scales. Here we describe two individual computational models based on in vivo and in vitro studies which, when incorporated into a single robust multiscale model, will provide information on the role of erythrocyte-released ATP in perfusion distribution in skeletal muscle under both physiological and pathophysiological conditions. Healthy human erythrocytes exposed to low O2 tension release ATP via a well characterized signaling pathway requiring activation of the G-protein, Gi, and adenylyl cyclase leading to increases in cAMP. This cAMP then activates PKA and subsequently CFTR culminating in ATP release via pannexin 1. A critical control point in this pathway is the level of cAMP which is regulated by pathway-specific phosphodiesterases. Using time constants (~100 ms) that are consistent with measured erythrocyte ATP release, we have constructed a dynamic model of this pathway. The model predicts levels of ATP release consistent with measurements obtained over a wide range of hemoglobin O2 saturations (sO2). The model further predicts how insulin, at concentrations found in pre-diabetes, enhances the activity of PDE3 and reduces intracellular cAMP levels leading to decreased low O2-induced ATP release from erythrocytes. The second model, which couples O2 and ATP transport in capillary networks, shows how intravascular ATP and the resulting conducted vasodilation are affected by local sO2, convection and ATP degradation. This model also predicts network-level effects of decreased ATP release resulting from elevated insulin levels. Taken together, these models lay the groundwork for investigating the systems biology of the regulation of microvascular perfusion distribution by erythrocyte-derived ATP.
登录
查看更多内容
影响因子：
4.1
作者：
Cazzaniga, Paolo;Pescini, Dario;Martegani, Enzo
通讯作者：
Martegani, Enzo
影响因子：
--
作者：
JACKSON, WF
通讯作者：
JACKSON, WF
红细胞：氧传感器和血管张力调节器。
影响因子：
8.4
作者：
Ellsworth, Mary L.;Ellis, Christopher G.;Goldman, Daniel;Stephenson, Alan H.;Dietrich, Hans H.;Sprague, Randy S.
通讯作者：
Sprague, Randy S.
DOI：
10.1152/ajpheart.00261.2008
发表时间：
2008-10-01
影响因子：
4.8
作者：
Arciero, Julia C.;Carlson, Brian E.;Secomb, Timothy W.
通讯作者：
Secomb, Timothy W.
DOI：
10.1046/j.1365-201x.2000.00708.x
发表时间：
2000-04-01
期刊：
ACTA PHYSIOLOGICA SCANDINAVICA
影响因子：
--
作者：
Ellsworth, ML
通讯作者：
Ellsworth, ML