Wu Florence T H, Stefanini Marianne O, Mac Gabhann Feilim, Kontos Christopher D, Annex Brian H, Popel Aleksander S
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Physiol Genomics. 2009 Jun 10;38(1):29-41. doi: 10.1152/physiolgenomics.00031.2009. Epub 2009 Apr 7.
Vascular endothelial growth factor (VEGF) signal transduction through the cell surface receptors VEGFR1 and VEGFR2 regulates angiogenesis-the growth of new capillaries from preexistent microvasculature. Soluble VEGF receptor-1 (sVEGFR1), a nonsignaling truncated variant of VEGFR1, has been postulated to inhibit angiogenic signaling via direct sequestration of VEGF ligands or dominant-negative heterodimerization with surface VEGFRs. The relative contributions of these two mechanisms to sVEGFR1's purported antiangiogenic effects in vivo are currently unknown. We previously developed a computational model for predicting the compartmental distributions of VEGF and sVEGFR1 throughout the healthy human body by simulating the molecular interaction networks of the VEGF ligand-receptor system as well as intercompartmental macromolecular biotransport processes. In this study, we decipher the dynamic processes that led to our prior prediction that sVEGFR1, through its ligand trapping mechanism alone, does not demonstrate significant steady-state antiangiogenic effects. We show that sVEGFR1-facilitated tissue-to-blood shuttling of VEGF accounts for a counterintuitive and drastic elevation in plasma free VEGF concentrations after both intramuscular and intravascular sVEGFR1 infusion. While increasing intramuscular VEGF production reduces free sVEGFR1 levels through increased VEGF-sVEGFR1 complex formation, we demonstrate a competing and opposite effect in which increased VEGF occupancy of neuropilin-1 (NRP1) and the corresponding reduction in NRP1 availability for internalization of sVEGFR1 unexpectedly increases free sVEGFR1 levels. In conclusion, dynamic intercompartmental transport processes give rise to our surprising prediction that VEGF trapping alone does not account for sVEGFR1's antiangiogenic potential. sVEGFR1's interactions with cell surface receptors such as NRP1 are also expected to affect its molecular interplay with VEGF.
血管内皮生长因子（VEGF）通过细胞表面受体VEGFR1和VEGFR2进行信号转导，调节血管生成——即从已有的微脉管系统生长出新的毛细血管。可溶性VEGF受体-1（sVEGFR1）是VEGFR1的一种无信号传导功能的截短变体，据推测它可通过直接隔离VEGF配体或与表面VEGFRs形成显性负性异二聚体来抑制血管生成信号传导。目前尚不清楚这两种机制对sVEGFR1在体内所谓的抗血管生成作用的相对贡献。我们之前通过模拟VEGF配体-受体系统的分子相互作用网络以及隔室间大分子生物转运过程，开发了一个计算模型，用于预测VEGF和sVEGFR1在健康人体中的隔室分布。在本研究中，我们解析了导致我们先前预测结果的动态过程，即sVEGFR1仅通过其配体捕获机制不会表现出显著的稳态抗血管生成作用。我们发现，在肌肉内和血管内输注sVEGFR1后，sVEGFR1促进的VEGF从组织到血液的穿梭导致血浆游离VEGF浓度出现违反直觉的急剧升高。虽然增加肌肉内VEGF的产生会通过增加VEGF-sVEGFR1复合物的形成来降低游离sVEGFR1水平，但我们证明了一种相反的竞争效应，即VEGF对神经纤毛蛋白-1（NRP1）的占有率增加以及相应的NRP1可用于sVEGFR1内化的可用性降低，意外地增加了游离sVEGFR1水平。总之，动态隔室间转运过程导致了我们令人惊讶的预测，即仅VEGF捕获并不能解释sVEGFR1的抗血管生成潜力。sVEGFR1与细胞表面受体（如NRP1）的相互作用也预计会影响其与VEGF之间的分子相互作用。
