Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Wiley Interdiscip Rev Syst Biol Med. 2010 Nov-Dec;2(6):694-707. doi: 10.1002/wsbm.92.
Vascular endothelial growth factor (VEGF) is a family of cytokines for which the dysregulation of expression is involved in many diseases; for some, excess VEGF causes pathological hypervascularization, while for others VEGF-induced vascular remodeling may alleviate ischemia and/or hypoxia. Anti-angiogenic therapies attacking the VEGF pathway have begun to live up to their promise for treatment of certain cancers and of age-related macular degeneration. However, the corollary is not yet true: in coronary artery disease and peripheral artery disease, clinical trials of pro-angiogenic VEGF delivery have not, so far, proven successful. The VEGF and VEGF-receptor system is complex, with at least five ligand genes, some encoding multiple protein isoforms and five receptor genes. A systems biology approach for designing pro-angiogenic therapies, using a combination of quantitative experimental approaches and detailed computational models, is essential to deal with this complexity and to understand the effects of drugs targeting the system. This approach allows us to learn from unsuccessful clinical trials and to design and test novel single therapeutics or combinations of therapeutics. Among the parameters that can be varied in order to determine optimal strategy are dosage, timing of multiple doses, route of administration, and the molecular target.
血管内皮生长因子（VEGF）是细胞因子家族的一种，其表达失调与许多疾病有关；在某些情况下，过量的 VEGF 会导致病理性血管过度生成，而在其他情况下，VEGF 诱导的血管重塑可能会缓解缺血和/或缺氧。针对 VEGF 途径的抗血管生成疗法已开始兑现其在治疗某些癌症和与年龄相关的黄斑变性方面的承诺。然而，反之尚未成为现实：在冠状动脉疾病和外周动脉疾病中，促血管生成 VEGF 传递的临床试验迄今为止并未证明是成功的。VEGF 和 VEGF 受体系统很复杂，至少有五个配体基因，其中一些基因编码多种蛋白同工型，还有五个受体基因。采用定量实验方法和详细的计算模型相结合的系统生物学方法来设计促血管生成疗法对于处理这种复杂性和理解针对该系统的药物的作用至关重要。这种方法使我们能够从不成功的临床试验中吸取教训，并设计和测试新的单一疗法或联合疗法。为了确定最佳策略，可以改变的参数包括剂量、多次剂量的时间、给药途径和分子靶标。
