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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable sustained delivery of recombinant VEGF164
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Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable sustained delivery of recombinant VEGF164

机译：持久的纤维蛋白基质可通过高度可调持续递送重组VEGF164来确保稳定和功能性的血管生成

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Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF164 was fused to a sequence derived from α2-plasmin inhibitor (α2-PI1–8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An α2-PI1–8–fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-α2-PI1–8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin-α2-PI1–8-VEGF164 allowed exquisitely dose-dependent angiogenesis: concentrations ≥25 μg/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01–5.0 μg/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-α2-PI1–8-VEGF164 was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis.
机译：通过血管内皮生长因子（VEGF）基因递送治疗血管新生的临床试验未能显示出疗效。主要挑战包括需要精确控制生长因子剂量和表达持续时间的体内分布。重组VEGF蛋白的递送可以克服这些问题，但是体内快速清除会阻止诱导的血管生成的稳定。在这里，我们开发了一种优化的血纤蛋白平台，用于控制重组VEGF的递送，以强烈诱导正常，稳定和功能性的血管生成。将鼠血管内皮生长因子164与来自α2-纤溶酶抑制剂（α2-PI1-8）的序列融合，该序列是凝血因子fXIIIa的底物，以使其共价交联成纤维蛋白水凝胶，仅通过酶促裂解释放。纤维蛋白溶解抑制剂抑肽酶的α2-PI1-8融合变体用于控制水凝胶降解速率，这决定了因子释放的持续时间和有效剂量。优化的抑肽酶-α2-PI1-8浓度可确保在4周内实现理想的降解。在这种情况下，血纤蛋白-α2-PI1-8-VEGF164可以实现剂量依赖性的血管生成：浓度≥25μg/ mL会引起广泛的异常血管结构，但是500倍的浓度范围（0.01–5.0μg/ mL）只能完全正常，成熟，无渗漏和灌注的毛细血管，在3个月后稳定。优化的纤维蛋白-α2-PI1-8-VEGF164的递送在缺血性后肢和伤口愈合模型中均具有治疗效果，可显着改善血管生成，组织灌注和治愈率。总之，这种优化的平台确保了（i）缺血组织中VEGF蛋白的控制和高度可调递送，以及（ii）稳定和功能性的血管生成，而无需引入遗传物质，并且治疗时间有限且可控。这些发现提出了改善治疗性血管生成的安全性和功效的策略。

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