纤溶酶原激活物抑制剂-1在动脉伤口愈合和新生内膜形成中的抑制作用：小鼠基因靶向和基因转移研究

Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice.

作者信息

Carmeliet P, Moons L, Lijnen R, Janssens S, Lupu F, Collen D, Gerard R D

机构信息

Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Belgium.

出版信息

Circulation. 1997 Nov 4;96(9):3180-91. doi: 10.1161/01.cir.96.9.3180.

DOI:10.1161/01.cir.96.9.3180

PMID:9386191

Abstract

BACKGROUND

Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury, suggesting that inhibition of plasmin generation might reduce arterial neointima formation. Therefore, we studied the consequences of plasminogen activator inhibitor-1 (PAI-1) gene inactivation and adenoviral PAI-1 gene transfer on arterial neointima formation.

METHODS AND RESULTS

Neointima formation was evaluated in PAI-1-deficient (PAI-1(-/-)) mice with perivascular electric or transluminal mechanical injury. PAI-1 deficiency improved vascular wound healing in both models: the cross-sectional neointimal area was 0.001+/-0.001 mm2 in PAI-1(+/+) and 0.016+/-0.008 mm2 in PAI-1(-/-) mice within 1 week after electric injury (P<.02) and 0.055+/-0.008 mm2 in PAI-1(+/+) and 0.126+/-0.006 mm2 in PAI-1(-/-) mice within 3 weeks after mechanical injury (P<.001). Proliferation of smooth muscle cells was not affected by PAI-1 deficiency. Topographic analysis of arterial wound healing after electric injury revealed that PAI-1(-/-) smooth muscle cells, originating from the uninjured borders, more rapidly migrated into the necrotic center of the arterial wound than wild-type smooth muscle cells. On the basis of immunostaining, PAI-1 expression was markedly upregulated during vascular wound healing. There were no genotypic differences in reendothelialization of the vascular wound. When PAI-1(-/-) mice were intravenously injected with replication-defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-dependent fashion up to to 61+/-8 microg/mL with 2x10(9) plaque-forming units (pfu) virus. Luminal stenosis was 35+/-13% in control AdRR5-treated (2x10(9) pfu) and suppressed to 5+/-5% in AdCMVPAI-1-treated (6x10(8) pfu) PAI-1(-/-) mice (P<.002).

CONCLUSIONS

By affecting cellular migration, PAI-1 plays an inhibitory role in vascular wound healing and arterial neointima formation after injury, and adenoviral PAI-1 gene transfer reduces arterial neointima formation in mice.

摘要

背景

纤溶酶原缺陷小鼠在血管损伤后显示出血管伤口愈合受损以及动脉内膜增生减少，这表明抑制纤溶酶生成可能会减少动脉内膜增生。因此，我们研究了纤溶酶原激活物抑制剂-1（PAI-1）基因失活和腺病毒介导的PAI-1基因转移对动脉内膜增生的影响。

方法与结果

在PAI-1缺陷（PAI-1(-/-)）小鼠中，通过血管周围电刺激或腔内机械损伤来评估内膜增生情况。在两种模型中，PAI-1缺陷均改善了血管伤口愈合：电损伤后1周内，PAI-1(+/+)小鼠的内膜横截面积为0.001±0.001mm²，PAI-1(-/-)小鼠为0.016±0.008mm²（P<0.02）；机械损伤后3周内，PAI-1(+/+)小鼠为0.055±0.008mm²，PAI-1(-/-)小鼠为0.126±0.006mm²（P<0.001）。PAI-1缺陷对平滑肌细胞增殖没有影响。电损伤后动脉伤口愈合的拓扑分析显示，源自未损伤边界的PAI-1(-/-)平滑肌细胞比野生型平滑肌细胞更快地迁移到动脉伤口的坏死中心。基于免疫染色，在血管伤口愈合过程中PAI-1表达明显上调。血管伤口的再内皮化在基因型上没有差异。当给PAI-1(-/-)小鼠静脉注射表达人PAI-1的复制缺陷型腺病毒（AdCMVPAI-1）时，血浆PAI-1抗原水平以剂量依赖方式增加，注射2×10⁹ 空斑形成单位（pfu）病毒时可达61±8μg/mL。在接受对照AdRR5处理（2×10⁹ pfu）的PAI-1(-/-)小鼠中，管腔狭窄为35±13%，而在接受AdCMVPAI-1处理（6×10⁸ pfu）的小鼠中，管腔狭窄被抑制至5±5%（P<0.002）。