Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA.
Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA.
Microcirculation. 2022 Feb;29(2):e12744. doi: 10.1111/micc.12744. Epub 2021 Dec 28.
We aim to quantitatively characterize the crosstalk between VEGF- and FGF-mediated angiogenic signaling and endothelial sprouting, to gain mechanistic insights and identify novel therapeutic strategies.
We constructed an experimentally validated hybrid agent-based mathematical model that characterizes endothelial sprouting driven by FGF- and VEGF-mediated signaling. We predicted the total sprout length, number of sprouts, and average length by the mono- and co-stimulation of FGF and VEGF.
The experimentally fitted and validated model predicts that FGF induces stronger angiogenic responses in the long-term compared with VEGF stimulation. Also, FGF plays a dominant role in the combination effects in endothelial sprouting. Moreover, the model suggests that ERK and Akt pathways and cellular responses contribute differently to the sprouting process. Last, the model predicts that the strategies to modulate endothelial sprouting are context-dependent, and our model can identify potential effective pro- and anti-angiogenic targets under different conditions and study their efficacy.
The model provides detailed mechanistic insight into VEGF and FGF interactions in sprouting angiogenesis. More broadly, this model can be utilized to identify targets that influence angiogenic signaling leading to endothelial sprouting and to study the effects of pro- and anti-angiogenic therapies.
我们旨在定量描述 VEGF 和 FGF 介导的血管生成信号与内皮芽生之间的串扰，以深入了解机制并确定新的治疗策略。
我们构建了一个经过实验验证的混合基于代理的数学模型，该模型描述了由 FGF 和 VEGF 介导的信号驱动的内皮芽生。我们通过 FGF 和 VEGF 的单刺激和共刺激预测了总芽长、芽数和平均长度。
经过实验拟合和验证的模型预测，与 VEGF 刺激相比，FGF 在长期内会引起更强的血管生成反应。此外，FGF 在内皮芽生的组合效应中起主导作用。此外，该模型表明 ERK 和 Akt 通路和细胞反应对芽生过程的贡献不同。最后，该模型预测，调节内皮芽生的策略是上下文相关的，我们的模型可以在不同条件下识别潜在的有效促血管生成和抗血管生成靶点，并研究它们的疗效。
该模型提供了关于 VEGF 和 FGF 在芽生血管生成中相互作用的详细机制见解。更广泛地说，该模型可用于识别影响导致内皮芽生的血管生成信号的靶点，并研究促血管生成和抗血管生成治疗的效果。
