Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Biophys J. 2013 May 21;104(10):2295-306. doi: 10.1016/j.bpj.2013.03.052.
Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
血管内皮细胞产生的一氧化氮（NO）是一种强效的血管扩张剂和抗炎介质。调节内皮衍生的 NO 的产生是一项复杂的任务，涉及到多个信号转导和遗传途径，这些途径可被多种体液和生物力学刺激所激活。为了全面理解实验中观察到的丰富多样的反应，有必要同时考虑到这些途径的综合作用。在本文中，我们汇集了之前提出的四种用于剪切力诱导 NO 产生的定量分子途径。在这些途径中，内皮型一氧化氮合酶通过以下方式被激活：1）钙离子释放，2）磷酸化反应，3）蛋白表达增强。我们在这些激活途径的基础上添加了第四个途径，即描述内皮型一氧化氮合酶及其各种蛋白伴侣实际产生 NO 的途径。这些途径被组合并使用 CytoSolve 进行了模拟，CytoSolve 是一种用于组合独立途径计算的计算环境。该综合模型能够描述在施加流体剪切力后，NO 产生随时间的变化。该模型还可用于预测在介入药理学或遗传学变化后对系统的特定影响。重要的是，该模型反映了目前对 NO 系统的理解，为以累加方式聚合信息提供了一个平台。
