The vascular endothelial growth factor (VEGF) family of cytokines is involved in the maintenance of existing adult blood vessels as well as in angiogenesis, the sprouting of new vessels. To study the proangiogenic activation of VEGF receptors (VEGFRs) by VEGF family members in skeletal muscle, we develop a computational model of VEGF isoforms (VEGF(121), VEGF(165)), their cell surface receptors, and the extracellular matrix in in vivo tissue. We build upon our validated model of the biochemical interactions between VEGF isoforms and receptor tyrosine kinases (VEGFR-1 and VEGFR-2) and nonsignaling neuropilin-1 coreceptors in vitro. The model is general and could be applied to any tissue; here we apply the model to simulate the transport of VEGF isoforms in human vastus lateralis muscle, which is extensively studied in physiological experiments. The simulations predict the distribution of VEGF isoforms in resting (nonexercising) muscle and the activation of VEGFR signaling. Little of the VEGF protein in muscle is present as free, unbound extracellular cytokine; the majority is bound to the cell surface receptors or to the extracellular matrix. However, interstitial sequestration of VEGF(165) does not affect steady-state receptor binding. In the absence of neuropilin, VEGF(121) and VEGF(165) behave similarly, but neuropilin enhances the binding of VEGF(165) to VEGFR-2. This model is the first to study VEGF tissue distribution and receptor activation in human muscle, and it provides a platform for the design and evaluation of therapeutic approaches.

译文

:细胞因子的血管内皮生长因子(VEGF)家族与现有成人血管的维护以及血管生成,新血管的萌发有关。为了研究骨骼肌中VEGF家族成员对VEGF受体(VEGFRs)的促血管生成激活作用,我们建立了VEGF同种型(VEGF(121),VEGF(165)),它们的细胞表面受体和细胞外基质的计算模型。体内组织。我们建立了我们的体外VEGF同工型和受体酪氨酸激酶(VEGFR-1和VEGFR-2)和无信号Neuropilin-1共受体之间的生化相互作用的验证模型。该模型是通用模型,可以应用于任何组织。在这里,我们应用该模型来模拟VEGF同工型在人股外侧肌中的运输,这在生理实验中已得到广泛研究。模拟预测了静息(非运动)肌肉中VEGF亚型的分布和VEGFR信号的激活。肌肉中很少有VEGF蛋白以游离的,未结合的细胞外细胞因子的形式存在。大多数与细胞表面受体或细胞外基质结合。但是,间质隔离VEGF(165)不会影响稳态受体结合。在没有神经纤毛蛋白的情况下,VEGF(121)和VEGF(165)的行为相似,但是神经纤毛蛋白会增强VEGF(165)与VEGFR-2的结合。该模型是第一个研究人肌肉中VEGF组织分布和受体激活的模型,它为设计和评估治疗方法提供了平台。

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