Cell signaling model for arterial mechanobiology
Cell signaling model for arterial mechanobiology
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DOI：
10.1371/journal.pcbi.1008161
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发表时间：
2020-08-01
影响因子：
4.3
通讯作者：
Humphrey, Jay D.
中科院分区：
文献类型：
--
作者：
Irons, Linda;Humphrey, Jay D.
生物软组织的特点是不断产生和去除材料，这赋予它们适应其生化和生物力学环境变化的显着能力。对于动脉，机械刺激主要由血压或流量的变化引起，而生化变化由多种因素引起，包括药物干预。为了了解动脉特性在健康状态下是如何维持的，或者它们在疾病中是如何适应或不适应的，我们必须更好地了解这些不同的刺激如何影响物质周转。细胞外基质受到机械传感和机械调节的严格调控，因此细胞信号传导，因此我们提出了一个计算模型的血管壁内的相关信号传导途径，其目的是预测响应于三个主要输入的壁组成和功能的变化：压力诱导的壁应力，流动诱导的壁剪切应力和外源性血管紧张素II。我们从文献中获得了一系列实验研究的定性协议，并提供了说明性的例子，展示了如何使用这些模型来进一步了解动脉remodeling.Arterial生长和重塑在组织水平上是由细胞和亚细胞水平上的机械生物学过程驱动的。虽然人们普遍认为细胞寻求促进组织的稳态，以响应生化和生物力学的线索，如增加高血压的壁应力，这些线索转化为组织的维护，适应或适应不良的方式还远未了解。在本文中，我们提出了一个基于逻辑的计算模型的细胞信号在动脉壁内，旨在预测细胞外基质周转和细胞表型的变化，压力引起的壁应力，流动引起的壁剪切应力，和外源性来源的血管紧张素II，特别是在小鼠模型的高血压。我们在细胞和组织水平上模拟了文献中的一些实验，涉及单个或组合输入，并在大多数情况下实现了高质量的一致性。此外，我们还演示了这种建模方法的实用性，用于模拟信令网络中各个节点的变更（在这种情况下是击倒）。对细胞信号传导的持续建模将有助于改善对健康和疾病中动脉生长和重塑的机制理解，并且在考虑潜在的药理学干预时至关重要。
Author summary Biological soft tissues are characterized by continuous production and removal of material, which endows them with a remarkable ability to adapt to changes in their biochemical and biomechanical environments. For arteries, mechanical stimuli result primarily from changes in blood pressure or flow, and biochemical changes are induced by multiple factors, including pharmacological intervention. In order to understand how arterial properties are maintained in health, or how they adapt or fail to adapt in disease, we must understand better how these diverse stimuli affect material turnover. Extracellular matrix is tightly regulated by mechano-sensing and mechano-regulation, and therefore cell signaling, thus we present a computational model of relevant signaling pathways within the vascular wall, with the aim of predicting changes in wall composition and function in response to three main inputs: pressure-induced wall stress, flow-induced wall shear stress, and exogenous angiotensin II. We obtain qualitative agreement with a range of experimental studies from the literature, and provide illustrative examples demonstrating how such models can be used to further our understanding of arterial remodeling.Arterial growth and remodeling at the tissue level is driven by mechanobiological processes at cellular and sub-cellular levels. Although it is widely accepted that cells seek to promote tissue homeostasis in response to biochemical and biomechanical cues-such as increased wall stress in hypertension-the ways by which these cues translate into tissue maintenance, adaptation, or maladaptation are far from understood. In this paper, we present a logic-based computational model for cell signaling within the arterial wall, aiming to predict changes in extracellular matrix turnover and cell phenotype in response to pressure-induced wall stress, flow-induced wall shear stress, and exogenous sources of angiotensin II, with particular interest in mouse models of hypertension. We simulate a number of experiments from the literature at both the cell and tissue level, involving single or combined inputs, and achieve high qualitative agreement in most cases. Additionally, we demonstrate the utility of this modeling approach for simulating alterations (in this case knockdowns) of individual nodes within the signaling network. Continued modeling of cellular signaling will enable improved mechanistic understanding of arterial growth and remodeling in health and disease, and will be crucial when considering potential pharmacological interventions.