Vascular Endothelial Growth Factor-Angiopoietin Chimera With Improved Properties for Therapeutic Angiogenesis
Vascular Endothelial Growth Factor-Angiopoietin Chimera With Improved Properties for Therapeutic Angiogenesis
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DOI：
10.1161/circulationaha.112.127472
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发表时间：
2013-01-29
期刊：
影响因子：
37.8
通讯作者：
Alitalo, Kari
中科院分区：
文献类型：
--
作者：
Anisimov, Andrey;Tvorogov, Denis;Alitalo, Kari
背景-心血管疾病中的组织缺血治疗对促血管生成治疗分子的需求尚未得到满足。然而，血管生成的主要诱导剂如血管内皮生长因子(VEGF/VEGF-A)具有副作用，限制了它们在体内的治疗作用，特别是在高浓度时。血管生成素-1被认为是一种血管稳定因子，可以抑制血管内皮生长因子的固有特性，促进血管渗漏。在这项研究中，我们设计并测试了由血管内皮生长因子受体结合部分和血管生成素-1组成的嵌合分子的血管生成特性。我们的目标是将这两种因子的活性结合到一个分子中，便于在靶组织中传递和表达。方法和结果-VEGF-Angiopoietin-1(VA1)嵌合蛋白同时与VEGF受体-2和Tie2结合，并诱导这两种受体的激活。对VA1和VEGF的详细分析表明，在VEGF受体-2激活和内吞、下游激酶激活和VE-钙粘附素内化的动力学方面存在差异。将VA1转基因导入小鼠骨骼肌，可增加血流量，增强血管生成。VA1在挽救肢体缺血灌流方面也非常有效。然而，VA1引起的血浆蛋白泄漏和髓系炎症细胞募集较VEGF少。结论：血管生成素-1嵌合体是一种有效的血管生成因子，可激活血管内皮生长因子受体-2的激活，减少血管渗漏，减轻组织炎症，改善缺血肌肉的血流灌注。VA1的这些特性使其成为一种有吸引力的治疗工具。(发行量。2013；127：424-434。)
Background-There is an unmet need for proangiogenic therapeutic molecules for the treatment of tissue ischemia in cardiovascular diseases. However, major inducers of angiogenesis such as vascular endothelial growth factor (VEGF/VEGF-A) have side effects that limit their therapeutic utility in vivo, especially at high concentrations. Angiopoietin-1 has been considered to be a blood vessel stabilization factor that can inhibit the intrinsic property of VEGF to promote vessel leakiness. In this study, we have designed and tested the angiogenic properties of chimeric molecules consisting of receptor-binding parts of VEGF and angiopoietin-1. We aimed at combining the activities of both factors into 1 molecule for easy delivery and expression in target tissues.Methods and Results-The VEGF-angiopoietin-1 (VA1) chimeric protein bound to both VEGF receptor-2 and Tie2 and induced the activation of both receptors. Detailed analysis of VA1 versus VEGF revealed differences in the kinetics of VEGF receptor-2 activation and endocytosis, downstream kinase activation, and VE-cadherin internalization. The delivery of a VA1 transgene into mouse skeletal muscle led to increased blood flow and enhanced angiogenesis. VA1 was also very efficient in rescuing ischemic limb perfusion. However, VA1 induced less plasma protein leakage and myeloid inflammatory cell recruitment than VEGF. Furthermore, angioma-like structures associated with VEGF expression were not observed with VA1.Conclusions-The VEGF-angiopoietin-1 chimera is a potent angiogenic factor that triggers a novel mode of VEGF receptor-2 activation, promoting less vessel leakiness, less tissue inflammation, and better perfusion in ischemic muscle than VEGF. These properties of VA1 make it an attractive therapeutic tool. (Circulation. 2013;127:424-434.)