Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis
Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis
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DOI：
10.1172/jci200418420
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发表时间：
2004-02-01
影响因子：
15.9
通讯作者：
Blau, HM
中科院分区：
文献类型：
--
作者：
Ozawa, CR;Banfi, A;Blau, HM
VEGF的长期组成性表达用于治疗性血管生成的用途可能受到异常血管和血管瘤生长的限制。我们通过将组成型表达VEGF（164）的成肌细胞植入成年小鼠的肌肉中，研究了VEGF剂量与新形成血管的形态和功能之间的关系。通过减少植入的VEGF成肌细胞总数来减少VEGF剂量并不能预防血管异常。然而，当植入均匀表达不同水平VEGF的成肌细胞的克隆群体时，发现正常和异常血管生成之间的阈值。表达低至中等水平VEGF的克隆成肌细胞诱导稳定的、均匀大小的周细胞包被的毛细血管的生长，所述毛细血管不渗漏并且变得不依赖于VEGF，如用有效VEGF阻断剂VEGF-Trap（RIR 2）处理所示。相反，表达高水平VEGF的克隆诱导血管瘤。值得注意的是，当不同的克隆群体混合时，即使是一小部分具有高VEGF产量的细胞也足以引起血管瘤生长。这些结果首次表明，我们的知识，VEGF诱导的血管生成是否正常或异常的关键决定因素是分泌的生长因子的微环境量，而不是总剂量。当维持低于阈值微环境水平时，VEGF的长期连续递送可导致正常的血管生成，而无需其他外源性生长因子。
Use of long-term constitutive expression of VEGF for therapeutic angiogenesis maybe limited by the growth of abnormal blood vessels and hemangiomas. We investigated the relationship between VEGF dosage and the morphology and function of newly formed blood vessels by implanting retrovitally transduced myoblasts that constitutively express VEGF(164) into muscles of adult mice. Reducing VEGF dosage by decreasing the total number of VEGF myoblasts implanted did not prevent vascular abnormalities. However, when clonal populations of myoblasts homogeneously expressing different levels of VEGF were implanted, a threshold between normal and aberrant angiogenesis was' found. Clonal myoblasts that expressed low to medium levels of VEGF induced growth of stable, pericyte-coated capillaries of uniform size that were not leaky and became VEGF independent, as Shown by treatment with the potent VEGF blocker VEGF-Trap(RIR2). In contrast, clones that expressed high levels of VEGF induced hemangiomas. Remarkably, when different clonal populations were mixed, even a small proportion of cells with high production of VEGF was sufficient to cause hemangioma growth. These results show for the first time to our knowledge that the key determinant of whether VEGF-induced angiogenesis is normal or aberrant is the microenvironmental amount of growth factor secreted, rather than the overall dose. Long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal angiogenesis without other exogenous growth factors.