Inhibition of TIMP1 enhances angiogenesis in vivo and cell migration in vitro
Inhibition of TIMP1 enhances angiogenesis in vivo and cell migration in vitro
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DOI：
10.1016/s0026-2862(02)00026-2
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发表时间：
2003-01-01
影响因子：
3.1
通讯作者：
Puolakkainen, P
中科院分区：
文献类型：
--
作者：
Reed, MJ;Koike, T;Puolakkainen, P
新生血管对三维基质的侵袭在一定程度上是由基质金属蛋白酶（MMPs）及其抑制剂组织金属蛋白酶抑制剂（TIMPs）控制的。我们验证了这样的假设：通过TIMP1的特异性阻断抗体，增加MMP活性会增强纤维血管侵入PVA海绵。在体内，TIMP1的抑制使血管生成侵袭量增加了一倍（侵袭面积百分比为33.5 +/- 3.5 vs 16.9 +/- 9.5, P = 0.003）。TIMP1的阻断抗体并没有增加海绵植入物中增殖的细胞比例，强调了迁移的重要性。在体外，经抗体处理的人微血管内皮细胞（hmEC）和真皮成纤维细胞没有分泌更多的胶原酶，但在I型胶原上迁移的距离明显更远（迁移距离增加26.6 +/- 9.4%,P = 0.003）。暴露于TIMP1阻断抗体的人皮肤微血管内皮细胞表现出细胞形状的显着变化，变为更细长的形态。综上所述，抑制TIMP1在体内增加了血管生成成PVA海绵，并在体外增强了真皮hmEC和成纤维细胞对I型胶原的迁移。我们提出阻断TIMP1通过增加纤维血管侵袭过程中的细胞运动性来促进血管生成。(C) 2003 Elsevier Science（美国）版权所有。
Neovascular invasion into a 3-dimensional matrix is controlled, in part, by matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). We tested the hypothesis that increasing MMP activity, via a specific blocking antibody to TIMP1, would enhance fibrovascular invasion into a PVA sponge. In vivo, inhibition of TIMP1 doubled the amount of angiogenic invasion (percentage area of invasion 33.5 +/- 3.5 vs 16.9 +/- 9.5, P = 0.003). The blocking antibody to TIMP1 did not increase the proportion of cells that were proliferating in the sponge implants, underscoring the importance of migration. In vitro, human microvascular endothelial cells (hmEC) and dermal fibroblasts treated with the antibody did not secrete greater amounts of collagenase but migrated significantly farther on collagen I (increase in distance migrated 26.6 +/- 9.4%, P = 0.003). Human dermal microvascular endothelial cells exposed to the TIMP1 blocking antibody exhibited a significant change in cell shape to a more elongated morphology. In conclusion, inhibition of TIMP1 increased angiogenesis into a PVA sponge in vivo and enhanced the migration of dermal hmEC and fibroblasts on collagen I in vitro. We propose that blocking TIMP1 improves angiogenesis by increasing cell motility during fibrovascular invasion. (C) 2003 Elsevier Science (USA). All rights reserved.