血管生成中芽形成的综合模型：在动态茎尖细胞选择中耦合VEGFA-Notch信号传导
Integrative modeling of sprout formation in angiogenesis: coupling the VEGFA-Notch signaling in a dynamic stalk-tip cell selection
摘要：
在血管生成过程中，由迁移的内皮尖端细胞领导的新血管从先前存在的血管中发芽。已知这一过程同时受两条信号通路调节，即血管内皮生长因子A（VEGFA）和Notch-Delta。细胞外VEGFA激活附近内皮细胞中的细胞内Notch-Delta途径，这导致内皮（茎、尖）分化。视网膜星形胶质细胞似乎通过分泌VEGFA在极化新芽中起着至关重要的作用。新生小鼠中的\emph{In vivo}视网膜血管生成实验产生了每日细胞计数的定量数据和在富含纤连蛋白的基质上扩展的血管网的形态学数据。基于这组数据和其他现有的数据，我们开发了一个基于细胞的，多尺度的数学模型，使用细胞Potts模型框架调查芽进化整合VEGFA和Notch-Delta信号通路。该模型包括三个层次的描述：细胞内，细胞间和细胞外。从一个单一的星形胶质细胞嵌入在富含纤维连接蛋白的基质，我们使用该模型来评估不同的情况下，VEGFA水平及其与基质蛋白的相互作用。模拟结果表明，星形胶质细胞衍生的VEGFA梯度与异质ECM一起再现发芽形态，并且在出生后7天的小鼠视网膜中的延伸速度与实验数据一致。结果还再现经验观察萌芽血管生成，包括吻合，动态尖端细胞竞争，和芽消退的Notch封锁的结果。
英文摘要：
During angiogenesis, new blood vessels headed by a migrating endothelial tip cell sprout from pre-existing ones. This process is known to be regulated by two signaling pathways concurrently, vascular endothelial growth factor A (VEGFA) and Notch-Delta. Extracellular VEGFA activates the intracellular Notch-Delta pathway in nearby endothelial cells which results in endothelial (stalk, tip) differentiation. Retinal astrocytes appear to play a crucial role in polarizing new sprouts by secreting VEGFA. \emph{In vivo} retinal angiogenesis experiments in neonatal mouse generated quantitative data on daily cell counts and morphological data of vascular network expanding over fibronectin-rich matrix. Based on this set of data and other existing ones, we developed a cell-based, multiscale mathematical model using the cellular Potts model framework to investigate the sprout evolution by integrating the VEGFA and Notch-Delta signaling pathways. The model incorporates three levels of description: intracellular, intercellular, and extracellular. Starting with a single astrocyte embedded in a fibronectin-rich matrix, we use the model to assess different scenarios regarding VEGFA levels and its interaction with matrix proteins. Simulation results suggest that astrocyte-derived VEGFA gradients along with heterogeneous ECM reproduces sprouting morphology, and the extension speed is in agreement with experimental data in 7 days postnatal mouse retina. Results also reproduce empirical observations in sprouting angiogenesis, including anastomosis, dynamic tip cell competition, and sprout regression as a result of Notch blockade.
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