Positive effect of treatment with synthetic steroid hormone tibolon on intimal hyperplasia and restenosis after experimental endothelial injury of rabbit carotid artery
Positive effect of treatment with synthetic steroid hormone tibolon on intimal hyperplasia and restenosis after experimental endothelial injury of rabbit carotid artery
复制标题
DOI：
10.1159/000076646
复制
发表时间：
2004-01-01
影响因子：
1.6
通讯作者：
Huk, I
中科院分区：
文献类型：
--
作者：
Nanobashvili, J;Prager, M;Huk, I
背景：雌激素可抑制动脉内膜增生及继发的再狭窄。我们研究了合成类固醇激素Tibolon在体内对内膜增生和再狭窄的影响，以及(B)在体外对内皮型一氧化氮合酶(ENOS)、血管内皮生长因子(VEGF)的产生、内皮细胞的增殖和凋亡的影响。方法：采用颈动脉球囊损伤动物模型，观察泰博隆(0.1 mg/kg体重，术前3天和术后3周，每日1次)对颈动脉球囊损伤后新生内膜形成(形态计量学)和动脉壁损伤(定性组织学)的影响。在人脐静脉内皮细胞(HUVEC)和人微血管内皮细胞(HMEC-1)中，用酶联免疫吸附试验(EL ISA)检测替博隆(0.1mug/ml)对eNOS和VEGF的影响。用血管内皮生长因子(165)诱导细胞增殖，用BrdU掺入法检测细胞增殖，用DNA片段化比色法检测细胞凋亡率。结果：球囊损伤可导致新生内膜形成，颈动脉壁损伤明显。经替博隆治疗后，管腔面积增大，内膜面积和内膜中层比减小，促进了受损血管壁的良好修复。在体外，Tibolon处理不影响HUVEC eNOS蛋白的表达和细胞的增殖率，但使内皮细胞的凋亡率减少约40%。此外，该治疗还抑制了基础水平和IL-1β刺激的HMEC-1中血管内皮生长因子的合成。结论：替博龙治疗可抑制颈动脉球囊损伤后新生内膜的形成，促进损伤管壁的良好修复。这一积极作用似乎与内皮细胞存活率的改善有关，可能导致一氧化氮的产生增加。这也可能与血管内皮细胞生长因子生成减少有关。版权所有(C)2004 S.Karger AG，巴塞尔。
Background: Arterial intimal hyperplasia and following restenosis may be inhibited by estrogens. We investigated the effect of a synthetic steroid hormone, Tibolon: ( a) on intima hyperplasia and restenosis in vivo, and (b) on production of endothelial nitric oxide synthase ( eNOS), vascular endothelial growth factor ( VEGF), endothelial cell proliferation and apoptosis in vitro. Methods: Influence of Tibolon treatment (0.1 mg/kg body weight, during 3 days before and 3 weeks after the operation as a drinking solution once daily) on neointimal formation ( measured by morphometry) and arterial wall damage ( by qualitative histology) were investigated in vivo using an animal model of balloon injury of carotid artery. In human umbilical vein endothelial cells ( HUVEC) and human microvascular endothelial cells (HMEC-1), the effect of Tibolon ( 0.1 mug/ml) on eNOS and VEGF was assessed by ELISA. Cell proliferation was induced by VEGF(165) and measured by BrdU incorporation assay, cell apoptosis was detected colorimetrically measuring DNA fragmentation. Results: Balloon injury resulted in neointima formation and prominent damage of the carotid artery wall. Treatment with Tibolon increased luminal area, decreased intimal area and intima to media ratio, and promoted better reparation of damaged vessel wall. In vitro, Tibolon treatment did not influence the expression of eNOS protein in HUVEC as well as cell proliferation rate but reduced apoptosis of endothelial cells by about 40%. Additionally, this treatment suppressed basal and IL-1beta-stimulated synthesis of VEGF in HMEC-1. Conclusions: Tibolon treatment suppressed neointimal formation and promoted better reparation of damaged vessel wall in carotid artery after balloon injury. This positive effect seems to be associated with improved endothelial cell survival resulting possibly in increased NO production. It might be also related to the decrease of VEGF generation. Copyright (C) 2004 S. Karger AG, Basel.