Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Angiogenesis. 2017 Aug;20(3):399-408. doi: 10.1007/s10456-017-9556-7. Epub 2017 Apr 10.
Therapeutic angiogenesis is an experimental frontier in vascular biology that seeks to deliver angiogenic growth factors to ischemic or injured tissues to promote targeted formation of new blood vessels as an alternative approach to surgical revascularization procedures. Vascular endothelial growth factor (VEGF) is a potent angiogenic signal protein that is locally upregulated at sites of tissue injury. However, therapies aimed at increasing VEGF levels experimentally by injecting VEGF gene or protein failed to improve outcomes in human trials in part due to its short half-life and systemic toxicity. We recently designed a novel 12-amino acid peptide (PR1P) whose sequence was derived from an extracellular VEGF-binding domain of the pro-angiogenic glycoprotein prominin-1. In this study, we characterized the molecular binding properties of this novel potential therapeutic for targeted angiogenesis and provided the foundation for its use as an angiogenic molecule that can potentiate endogenous VEGF. We showed that PR1P bound VEGF directly and enhanced VEGF binding to endothelial cells and to VEGF receptors VEGFR2 and neuropilin-1. PR1P increased angiogenesis in the murine corneal micropocket assay when combined with VEGF, but had no activity without added VEGF. In addition, PR1P also enhanced angiogenesis in murine choroidal neovascularization and wound-healing models and augmented reperfusion in a murine hind-limb ischemia model. Together our data suggest that PR1P enhanced angiogenesis by potentiating the activity of endogenous VEGF. In so doing, this novel therapy takes advantage of endogenous VEGF gradients generated in injured tissues and may improve the efficacy of and avoid systemic toxicity seen with previous VEGF therapies.
治疗性血管生成是血管生物学中的一个实验前沿领域，旨在将血管生成生长因子递送到缺血或受损组织中，以促进靶向形成新的血管，作为手术血运重建程序的替代方法。血管内皮生长因子（VEGF）是一种有效的血管生成信号蛋白，在组织损伤部位会局部上调。然而，通过注射 VEGF 基因或蛋白来实验性地增加 VEGF 水平的治疗方法在人类临床试验中未能改善结果，部分原因是其半衰期短和全身毒性。我们最近设计了一种新型的 12 个氨基酸肽（PR1P），其序列来源于促血管生成糖蛋白 prominin-1 的血管生成结合域的细胞外部分。在这项研究中，我们表征了这种新型潜在治疗药物的分子结合特性，为其作为一种能够增强内源性 VEGF 的血管生成分子的应用提供了基础。我们表明，PR1P 直接结合 VEGF，并增强 VEGF 与内皮细胞以及 VEGF 受体 VEGFR2 和神经纤毛蛋白-1 的结合。当与 VEGF 联合使用时，PR1P 增加了小鼠角膜微囊中的血管生成，但在没有添加 VEGF 的情况下没有活性。此外，PR1P 还增强了小鼠脉络膜新生血管形成和伤口愈合模型中的血管生成，并增强了小鼠后肢缺血模型中的再灌注。我们的数据表明，PR1P 通过增强内源性 VEGF 的活性来增强血管生成。通过这种方式，这种新型治疗方法利用了损伤组织中产生的内源性 VEGF 梯度，可能提高以前的 VEGF 治疗方法的疗效并避免其全身毒性。
