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ERK and Akt exhibit distinct signaling responses following stimulation by pro-angiogenic factors.
Cell Communication and Signaling ( IF 8.4 ) Pub Date : 2020-07-17 , DOI: 10.1186/s12964-020-00595-w
Min Song 1 , Stacey D Finley 1, 2, 3
Affiliation  

Angiogenesis plays an important role in the survival of tissues, as blood vessels provide oxygen and nutrients required by the resident cells. Thus, targeting angiogenesis is a prominent strategy in many different settings, including both tissue engineering and cancer treatment. However, not all of the approaches that modulate angiogenesis lead to successful outcomes. Angiogenesis-based therapies primarily target pro-angiogenic factors such as vascular endothelial growth factor-A (VEGF) or fibroblast growth factor (FGF) in isolation, and there is a limited understanding of how these promoters combine together to stimulate angiogenesis. Targeting one pathway could be insufficient, as alternative pathways may compensate, diminishing the overall effect of the treatment strategy. To gain mechanistic insight and identify novel therapeutic strategies, we have developed a detailed mathematical model to quantitatively characterize the crosstalk of FGF and VEGF intracellular signaling. The model focuses on FGF- and VEGF-induced mitogen-activated protein kinase (MAPK) signaling to promote cell proliferation and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, which promotes cell survival and migration. We fit the model to published experimental datasets that measure phosphorylated extracellular regulated kinase (pERK) and Akt (pAkt) upon FGF or VEGF stimulation. We validate the model with separate sets of data. We apply the trained and validated mathematical model to characterize the dynamics of pERK and pAkt in response to the mono- and co-stimulation by FGF and VEGF. The model predicts that for certain ranges of ligand concentrations, the maximum pERK level is more responsive to changes in ligand concentration compared to the maximum pAkt level. Also, the combination of FGF and VEGF indicates a greater effect in increasing the maximum pERK compared to the summation of individual effects, which is not seen for maximum pAkt levels. In addition, our model identifies the influential species and kinetic parameters that specifically modulate the pERK and pAkt responses, which represent potential targets for angiogenesis-based therapies. Overall, the model predicts the combination effects of FGF and VEGF stimulation on ERK and Akt quantitatively and provides a framework to mechanistically explain experimental results and guide experimental design. Thus, this model can be utilized to study the effects of pro- and anti-angiogenic therapies that particularly target ERK and/or Akt activation upon stimulation with FGF and VEGF.

中文翻译:

在促血管生成因子刺激后,ERK 和 Akt 表现出不同的信号反应。

血管生成在组织的存活中起着重要作用,因为血管提供常驻细胞所需的氧气和营养。因此,靶向血管生成是许多不同环境中的重要策略,包括组织工程和癌症治疗。然而,并非所有调节血管生成的方法都能带来成功的结果。基于血管生成的疗法主要针对促血管生成因子,如血管内皮生长因子-A (VEGF) 或成纤维细胞生长因子 (FGF),并且对这些启动子如何结合在一起刺激血管生成的了解有限。仅针对一种途径可能是不够的,因为替代途径可能会进行补偿,从而削弱治疗策略的整体效果。为了获得机械洞察力并确定新的治疗策略,我们开发了一个详细的数学模型来定量表征 FGF 和 VEGF 细胞内信号传导的串扰。该模型侧重于 FGF 和 VEGF 诱导的丝裂原活化蛋白激酶 (MAPK) 信号传导以促进细胞增殖和磷脂酰肌醇 3-激酶/蛋白激酶 B (PI3K/Akt) 通路,促进细胞存活和迁移。我们将模型拟合到已发表的实验数据集,这些数据集在 FGF 或 VEGF 刺激下测量磷酸化的细胞外调节激酶 (pERK) 和 Akt (pAkt)。我们使用单独的数据集验证模型。我们应用经过训练和验证的数学模型来表征 pERK 和 pAkt 响应 FGF 和 VEGF 的单刺激和共刺激的动力学。该模型预测,对于特定范围的配体浓度,与最大 pAkt 水平相比,最大 pERK 水平对配体浓度的变化更敏感。此外,与单个效应的总和相比,FGF 和 VEGF 的组合表明在增加最大 pERK 方面有更大的作用,这在最大 pAkt 水平上是看不到的。此外,我们的模型确定了专门调节 pERK 和 pAkt 反应的有影响的物种和动力学参数,它们代表了基于血管生成的疗法的潜在目标。总体而言,该模型定量预测了 FGF 和 VEGF 刺激对 ERK 和 Akt 的联合作用,并提供了一个框架来机械解释实验结果和指导实验设计。因此,
更新日期:2020-07-17
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