缺氧诱导因子-1a和血管内皮细胞生成因子在兔移植静脉再内皮化中的表达研究
摘要
缺氧诱导因子-1α(HIF-1α)、血管内皮细胞生长因子(VEGF)在血管生成表达中有重要意义,HIF-1α是缺氧状态下血管生成的核心调控因子,通过影响其他生长因子的表达参与血管生成的全过程。VEGF是血管生成初期关键性的生长因子,缺氧状态可以诱导VEGF大量表达。VEGF在血管生成中发挥重要作用,VEGF具有促血管内皮细胞分裂、增殖,增加血管的通透性,诱导内皮细胞Bcl-2基因表达,提高内皮细胞抗凋亡能力等作用。本实验通过检测缺氧诱导因子-1α(HIF-1α)和血管内皮细胞生成因子(VEGF)在兔颈总动脉内膜剥脱+颈前静脉自体静脉移植手术前后各期的表达以及移植静脉术后剥脱内膜段动脉管腔横截面积的变化,研究HIF-1α和VEGF在兔移植静脉再内皮化过程中的作用。
目的
探讨HIF-1α和VEGF的表达对大白兔移植静脉再内皮化的影响。
1、HIF-1α和VEGF在兔颈总动脉内膜剥脱+颈前静脉自体静脉移植手术前后各期的表达关系。
2、移植静脉术后剥脱内膜段动脉管腔横截面积的变化
方法
1、分组和制作动物模型6月龄成年雄性新西兰大白兔46只,随机分为两组,第一组10只,第二组36只(其中30只为试验必须动物,6只为备用)。均以普通饮食饲养一周后,采集第一组10只实验兔的血清分别采用酶联免疫吸附法(ELISA法)行HIF-1α和VEGF检测,然后取所有10只兔的左颈前静脉行HE染色做病理学检查,观察动脉血管腔面积。第二组36只大白兔均行左侧颈总动脉内膜剥脱+颈前静脉自体静脉移植术,制作再狭窄模型,术后以普通饮食饲养。于手术后7天、14天、30天三个时间点依次分别随机抽取10只实验兔采集血清用酶联免疫吸附法(ELISA法)行HIF-1α和VEGF检测,抽血后取该次试验10只兔剥脱内膜段动脉行HE染色做病理学实验,并观察动脉血管腔面积、内膜增生和平滑肌数量的动态变化。
2、病理学资料图像分析采用病理学图像分析系统对标本：兔移植静脉HE染色、Mason染色片进行形态学分析。
3、化学法分析分别于静脉移植手术前和手术后7天、14天、30天采血用ELISA法测量血清中HIF-1α和VEGF的水平。
结果
1、HIF-1α和VEGF各期的表达差别具有统计学意义(P<0.01)；HIF-1α和VEGF在兔自体静脉移植术后表达明显增加(P<0.01),其中在7天时最高,之后逐渐下降,在术后30天时仅稍高于正常。
2、HE染色结果显示剥脱内膜段动脉血管腔面积(LA)总体呈先逐渐缩小,于术后14天达最低值,然后逐渐增大趋势。
结论
1、本次实验中成功地制作了兔颈总动脉内膜剥脱+自体静脉移植术后再狭窄模型。
2、组织器官急性缺血缺氧期HIF-1α和VEGF表达迅速增高；随着时间延长,组织器官对缺血缺氧的适应,两因子浓度逐渐降低,本实验中观察到的HIF-1α和VEGF表达高峰出现在术后7天,且两指标在各期表达差别明显有统计学意义。
3、移植静脉术后血管重塑的早期HIF-1α和VEGF的高表达可促进受损血管内皮细胞(VEC)结构和功能的重建,维持动脉管腔面积；随着时间推移,HIF-1α和VEGF的表达逐渐减少,移植静脉术后剥脱内膜段动脉管腔逐渐缩小,于术后14天达到最小,然后逐渐增大,且动脉管腔面积在各期差别明显有统计学意义。
4、HIF-1α和VEGF表达高峰和移植静脉术后剥脱内膜段动脉管腔最小值分别出现在术后7天和14天,所以术后7-14天HIF-1α和VEGF表达的过早降低可能与移植静脉术后再狭窄有关。在各期HIF-1α和VEGF表水平均服从正态分布,经过Pearson相关分析存在强的正相关,相关系数r分别为0.901,0.832,0.779,0.863。
Hypoxia-inducible factor-la (HIF-la), vascular endothelial growth factor (VEGF) expression in angiogenesis of significance, HIF-la is a hypoxia state the core of regulation of angiogenesis factors, by influencing other growth factors Expression of the entire process involved in angiogenesis. VEGF is a critical early stage of angiogenesis growth factor, hypoxia may induce substantial expression of VEGF.VEGF is a critical early stage of angiogenesis growth factor, hypoxia may induce substantial expression of VEGF. VEGF in the angiogenesis play an important role, VEGF has vascular endothelial cell division, proliferation, increase vascular permeability, induce endothelial cell Bcl-2 gene expression, enhance the ability of endothelial cells in anti-apoptotic effect.In this study, by detecting hypoxia-inducible factor-la (HIF-la) and vascular endothelial growth factor (VEGF) in rabbit carotid artery endarterectomy +anterior vein autogenous vein graft and postoperative phases of expression and the vein graft after exfoliative endometrial changes in segmental artery lumen cross-sectional area to study the HIF-1αand VEGF in a rabbit vein graft re-endothelialization role in the process.
Objective
To investigate the HIF-1αand VEGF expression in pairs of rabbits vein graft re-endothelialization of impact.
1、HIF-la and VEGF in the rabbit carotid artery endarterectomy+anterior vein autogenous vein graft and postoperative phases of the expression of the relationship.
2、after stripping of vein graft intimal changes in segmental artery lumen cross-sectional area
Methods
1、group and the production of 6-month-old animal model 46 adult male New Zealand white rabbits were randomly divided into two groups, the first group of 10, the second group of 36 (including 30 for the trial to be animals, six of standby). Are based on ordinary food a week after feeding, collecting the first group of 10 rabbits were used in serum by enzyme-linked immunosorbent assay (ELISA) line of HIF-la and VEGF detection, and then take all 10 rabbits left cervical venous line HE staining do pathological examination to observe the arterial lumen area. The second group of 36 rabbits underwent left common carotid artery endarterectomy+ anterior vein autogenous vein graft, producing restenosis model,
An ordinary diet after feeding.7 days after the operation,14 days,30 days followed by three time points were randomly selected from 10 rabbits collected serum by enzyme-linked immunosorbent assay (ELISA) line of HIF-la and VEGF testing, blood tests after taking the 10 rabbits in paragraph artery intima stripping HE staining did pathology laboratory, and to observe the arterial lumen area, the number of intimal hyperplasia and smooth muscle dynamics.
2、pathological image analysis image analysis system using pathological specimens:Rabbit vein graft HE staining, Mason morphological analysis of stained films.
3、chemical analysis of vein graft, respectively, prior to surgery and 7 days after 14 days,30 days, blood serum by ELISA measurement of HIF-1αand VEGF levels.
Results
1、HIF-la and VEGF expression in each period with a significant correlation (P <0.01); HIF-1αand VEGF in the rabbit autologous vein graft expression was significantly increased (P <0.01), in which the highest in 7 days, followed by a gradual decreased 30 days after the operation is only slightly higher than normal.
2、HE staining showed intimal denudation arterial segment lumen area (LA) was the first overall diminishing, at the lowest value reached after 14 days and then gradually increasing trend.
Conclusion
1、this experiment has successfully produced a rabbit carotid artery endarterectomy and autogenous vein graft restenosis model.
2、tissues and organs in acute hypoxia-ischemia period of HIF-la and VEGF expression increased rapidly; with prolonged ischemia and hypoxia of tissues and organs adapt gradually reduced two-factor concentrations, this experiment the observed HIF-la and VEGF expression peaked at 7 days after operation.
3、after vein graft vascular remodeling in the early HIF-1αand VEGF can promote damage to the high expression of vascular endothelial cells (VEC) reconstruction of the structure and function to maintain the arterial lumen area; as time goes by, HIF-la and the the expression of VEGF gradually decreased after stripping of vein graft intimal segment arteries gradually narrowed to a minimum of 14 days after the operation, and then gradually increased.
4、HIF-la and VEGF expression after stripping peaks and vein graft intimal minimum segment arteries, respectively after 7 days in 14 days, so after 7-14 days of HIF-la and VEGF expression in early reduction may be related to the vein graft restenosis.
目的
探讨HIF-1α和VEGF的表达对大白兔移植静脉再内皮化的影响。
1、HIF-1α和VEGF在兔颈总动脉内膜剥脱+颈前静脉自体静脉移植手术前后各期的表达关系。
2、移植静脉术后剥脱内膜段动脉管腔横截面积的变化
方法
1、分组和制作动物模型6月龄成年雄性新西兰大白兔46只,随机分为两组,第一组10只,第二组36只(其中30只为试验必须动物,6只为备用)。均以普通饮食饲养一周后,采集第一组10只实验兔的血清分别采用酶联免疫吸附法(ELISA法)行HIF-1α和VEGF检测,然后取所有10只兔的左颈前静脉行HE染色做病理学检查,观察动脉血管腔面积。第二组36只大白兔均行左侧颈总动脉内膜剥脱+颈前静脉自体静脉移植术,制作再狭窄模型,术后以普通饮食饲养。于手术后7天、14天、30天三个时间点依次分别随机抽取10只实验兔采集血清用酶联免疫吸附法(ELISA法)行HIF-1α和VEGF检测,抽血后取该次试验10只兔剥脱内膜段动脉行HE染色做病理学实验,并观察动脉血管腔面积、内膜增生和平滑肌数量的动态变化。
2、病理学资料图像分析采用病理学图像分析系统对标本：兔移植静脉HE染色、Mason染色片进行形态学分析。
3、化学法分析分别于静脉移植手术前和手术后7天、14天、30天采血用ELISA法测量血清中HIF-1α和VEGF的水平。
结果
1、HIF-1α和VEGF各期的表达差别具有统计学意义(P<0.01)；HIF-1α和VEGF在兔自体静脉移植术后表达明显增加(P<0.01),其中在7天时最高,之后逐渐下降,在术后30天时仅稍高于正常。
2、HE染色结果显示剥脱内膜段动脉血管腔面积(LA)总体呈先逐渐缩小,于术后14天达最低值,然后逐渐增大趋势。
结论
1、本次实验中成功地制作了兔颈总动脉内膜剥脱+自体静脉移植术后再狭窄模型。
2、组织器官急性缺血缺氧期HIF-1α和VEGF表达迅速增高；随着时间延长,组织器官对缺血缺氧的适应,两因子浓度逐渐降低,本实验中观察到的HIF-1α和VEGF表达高峰出现在术后7天,且两指标在各期表达差别明显有统计学意义。
3、移植静脉术后血管重塑的早期HIF-1α和VEGF的高表达可促进受损血管内皮细胞(VEC)结构和功能的重建,维持动脉管腔面积；随着时间推移,HIF-1α和VEGF的表达逐渐减少,移植静脉术后剥脱内膜段动脉管腔逐渐缩小,于术后14天达到最小,然后逐渐增大,且动脉管腔面积在各期差别明显有统计学意义。
4、HIF-1α和VEGF表达高峰和移植静脉术后剥脱内膜段动脉管腔最小值分别出现在术后7天和14天,所以术后7-14天HIF-1α和VEGF表达的过早降低可能与移植静脉术后再狭窄有关。在各期HIF-1α和VEGF表水平均服从正态分布,经过Pearson相关分析存在强的正相关,相关系数r分别为0.901,0.832,0.779,0.863。
Hypoxia-inducible factor-la (HIF-la), vascular endothelial growth factor (VEGF) expression in angiogenesis of significance, HIF-la is a hypoxia state the core of regulation of angiogenesis factors, by influencing other growth factors Expression of the entire process involved in angiogenesis. VEGF is a critical early stage of angiogenesis growth factor, hypoxia may induce substantial expression of VEGF.VEGF is a critical early stage of angiogenesis growth factor, hypoxia may induce substantial expression of VEGF. VEGF in the angiogenesis play an important role, VEGF has vascular endothelial cell division, proliferation, increase vascular permeability, induce endothelial cell Bcl-2 gene expression, enhance the ability of endothelial cells in anti-apoptotic effect.In this study, by detecting hypoxia-inducible factor-la (HIF-la) and vascular endothelial growth factor (VEGF) in rabbit carotid artery endarterectomy +anterior vein autogenous vein graft and postoperative phases of expression and the vein graft after exfoliative endometrial changes in segmental artery lumen cross-sectional area to study the HIF-1αand VEGF in a rabbit vein graft re-endothelialization role in the process.
Objective
To investigate the HIF-1αand VEGF expression in pairs of rabbits vein graft re-endothelialization of impact.
1、HIF-la and VEGF in the rabbit carotid artery endarterectomy+anterior vein autogenous vein graft and postoperative phases of the expression of the relationship.
2、after stripping of vein graft intimal changes in segmental artery lumen cross-sectional area
Methods
1、group and the production of 6-month-old animal model 46 adult male New Zealand white rabbits were randomly divided into two groups, the first group of 10, the second group of 36 (including 30 for the trial to be animals, six of standby). Are based on ordinary food a week after feeding, collecting the first group of 10 rabbits were used in serum by enzyme-linked immunosorbent assay (ELISA) line of HIF-la and VEGF detection, and then take all 10 rabbits left cervical venous line HE staining do pathological examination to observe the arterial lumen area. The second group of 36 rabbits underwent left common carotid artery endarterectomy+ anterior vein autogenous vein graft, producing restenosis model,
An ordinary diet after feeding.7 days after the operation,14 days,30 days followed by three time points were randomly selected from 10 rabbits collected serum by enzyme-linked immunosorbent assay (ELISA) line of HIF-la and VEGF testing, blood tests after taking the 10 rabbits in paragraph artery intima stripping HE staining did pathology laboratory, and to observe the arterial lumen area, the number of intimal hyperplasia and smooth muscle dynamics.
2、pathological image analysis image analysis system using pathological specimens:Rabbit vein graft HE staining, Mason morphological analysis of stained films.
3、chemical analysis of vein graft, respectively, prior to surgery and 7 days after 14 days,30 days, blood serum by ELISA measurement of HIF-1αand VEGF levels.
Results
1、HIF-la and VEGF expression in each period with a significant correlation (P <0.01); HIF-1αand VEGF in the rabbit autologous vein graft expression was significantly increased (P <0.01), in which the highest in 7 days, followed by a gradual decreased 30 days after the operation is only slightly higher than normal.
2、HE staining showed intimal denudation arterial segment lumen area (LA) was the first overall diminishing, at the lowest value reached after 14 days and then gradually increasing trend.
Conclusion
1、this experiment has successfully produced a rabbit carotid artery endarterectomy and autogenous vein graft restenosis model.
2、tissues and organs in acute hypoxia-ischemia period of HIF-la and VEGF expression increased rapidly; with prolonged ischemia and hypoxia of tissues and organs adapt gradually reduced two-factor concentrations, this experiment the observed HIF-la and VEGF expression peaked at 7 days after operation.
3、after vein graft vascular remodeling in the early HIF-1αand VEGF can promote damage to the high expression of vascular endothelial cells (VEC) reconstruction of the structure and function to maintain the arterial lumen area; as time goes by, HIF-la and the the expression of VEGF gradually decreased after stripping of vein graft intimal segment arteries gradually narrowed to a minimum of 14 days after the operation, and then gradually increased.
4、HIF-la and VEGF expression after stripping peaks and vein graft intimal minimum segment arteries, respectively after 7 days in 14 days, so after 7-14 days of HIF-la and VEGF expression in early reduction may be related to the vein graft restenosis.
引文
[1]. Ross R. The pathogensis of atherosclerosis;A perspective for the 1990s. Nature 1993,362:801-809.
[2]. Ip JH, Fuster V. Syndromes of accelerated atherosclerosis:role of vascular injury and smooth muscle cell proliferation. Am Coll Cardiol.1990,15(7):1667-1687.
[3]. Chan AW, Chew DP, Lincoff AM. Update on pharmacology for restenosis.Curr Interv Cardiol Rep,2001,3:149-155.
[4]. Mintz GS, Weissman NJ, Teirstein PS, etal. Effect of intracoronary gamma-radiation therapy on in-stent restenosis:An intravascular ultrasound analysis from the GAMMA-lstudy.Circulation,2000,102:2915-2918.
[5]. Pugh CW,Ratcliffe PJ.Regulation of angiogenesis by hypoxia:role of the HIF systim[J].Nat Med,2003,9:677-684.
[6]. Mazure NM,Brahimi-Horn MC,Pouyssegur J.Proten kinases and thehypoxia-inducible factor-l,two switches in angiogenesis[J].Curr Pharm Des,2003,9:531-541.
[7].段小军,杨柳,周跃等.缺氧诱导因子促进血管生成的调控机制[J].中华创伤杂志,2004,20(8)：507-509.
[8]. Pugh CW,Ratcliffe PJ.Regulation of angiogenesis by hypoxia:role of the HIF system[J].Nat Med,2003,9:677-684.
[9]. Mazure NM,Brahimi-Horn MC,Pouyssegur J.Protein kinases and the hypoxia-inducible factor-l,two switches in angiogenesis[J].Curr Pharm Des,2003,9(7):531-541.
[10].6Hirot K.Hypoxia-inducible factor 1,a master transcription factor of cellular hypoxic gene expression[J].Anesth,2002,16:150-159.
[11]. Liu LX,Lu H,Luo Y,et al.Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1[J].Biochem Biophys Res Commun,2002,291:908-914.
[12]. 张勇,娄桂予,钱民章.建立兔高脂血症模型及动脉粥样硬化斑块的方法[J].遵义医学院报,2001,8,24：304
[13]. 郭延松,吴宗贵.鼠动脉粥样硬化模型复制方法的比较.中国动脉硬化杂志.2003,11(5)：465.
[14]. 李秋梅,王硕仁,赵明镜,等.家兔新型动脉粥样硬化狭窄模型的建立及其动态
观察[J].中国实验动物学报,2004,12(1)：26—28
[15]. Cottin Y, Kollum M,kolodgie FD, et al. Intravascular radiation accelerates atherosclerotic lesion formation of hyperc-holesterolemic rabbits[J]. Cardiovasc Radlat Med,2001,2(4):231—240
[16]. Plump AS, Smith JD. Severe hypereholes lerolemin and atheroselerosis in apolipoprotein E-deficient mice erealed by homologous recombination in ES cells. Cell, 1992.71,343
[17]. 张瑞华,余竹元,王卫群,等.肺炎衣原体感染与动脉粥样硬化动物模型研究新进展.海峡预防医学杂志,2002,8(3)：31—32.
[18]. Rubin EM. Isbids BY. Expression of human apolipoprotein A—1 in transgenic mice results in reduced plasma new high density lipoprotein size subclasses. Prec Nati Aead Sei USA.1991,353:265.
[19]. Ferrario CM.Use of angiotensin II receptor blockers in animal models of atherosclerosis. Am J Hypertens,2002,15(1 pt 2):9s—13s.
[20]. Varadi G, Mori Y, Mikala G, et al. Molecular determinations of Ca2+channel function and drug action.Trends Pharmacol Sci,1995,16(2):43-49.
[21]. Xie J, Guo Q, Zhu H, et al. Protein kinase C iota protects neural cells against apoptosis induced by amyloid beta-peptide.Brain Res Mol Brain Res,2000,82(1-2):107-113.
[22]. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Eng Med.1987;316(22):1371-1375.
[23]. Gibbons GH, Dzau V J. The Emerging Concept of Vascular Remodeling. N Eng Med.1994 330(20):1431—1438.
[24]. Tomasian D, Keaney. JF, Vite JA. Antioxidants and the bioaetivity of endothelitnn-derived nitric oxide. Cardivasc Res,2000,47(3):426-435
[25]. Dzau VJ, Gibbons GH, Mann M, Braun-Dullacus R. Future horizons in card-iovascul molecular therapeutics. Am Cardial,1997,80(9A):331—391
[26]. Lerman A, Cannon CR,Higano SH. et al Coronary vascular remodeling in asso-elation with endothelial dysfunction Am J Cardiol,1998.81:1105.1109
[27]. Tronc F, Wassef M, Esposito B. et al. Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol,1996,16:1256-1262.
[28]. Stein I,Itin A,Einat P,et al.Translation of vascular endothelial growth factor m RNA by inhternal ribosome entry:implications for translation under hypoxia[J].Mol Cell Bool,1998,18:3112-3119.
[29]. Gerber HP,Condorelli F,Park J,et al.Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes.Flt-l,but not Flk-1/KDR,is up-regulated by hypoxia[J].Biol Chem,1997,272:23659-23667.
[30]. Gassmann M,Chilov D,Wenger RH.Regulation of the hypoxia-inducible factor-1 alpha.ARNT is not necessary for hypoxic induction of HIF-1 alpha in the nucleus[J].Adv Exp Med Biol,2000,475:87-94.
[31]. Jiang BH,Zheng JZ,Leung SW,et al.Transactivation and inhibitory do mains of hypoxia inducible factor 1 alpha.Modulation of transcriptional activity byoxygen tension.[J]Biol Chem,1997,272;31:19253-19260.
[32]. Semenza GL.Hypoxia-inducible factor 1:control of oxygen homeostasis in health and disease[J].Pediatr Res,2001,49(5):614-617.
[33]. Richard DF, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the
[34]. induction of hypoxia2inducible factor-la in vascular smooth muscle cells. J Biol Chem,2000,275:26765-26771.
[35]. 杨镛,段志泉,张强,等.缺氧诱导因子21 α表达与移植静脉再内皮化关系的实验研究.中华医学杂志,2003,83：628-631.
[36]. Elson DA, Thurston G, Huang LE, et al. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing Hypoxia-inducible factor-la. Genes Dev,2001,15:2520-2532.
1. Gibbons GH, et al.The emerging concept of vascular remodeling N Engl J Med 1994; 330:1431-1438.
2. Nieolini FA, et al.Surg Clin NorthAm,1992;72(4):919—940.
3. Reidy MA et al.Atheroselerosis,1989;10(2):298—305.
4. Dilley RJ et al.Areh Surg,1988; 123(6):691—696.
5. Dilley RJ etal.Atherosclerosis1989;9(2):289—298.
6. Cox JL et al.Prog Cardilvasc Dis,1991;34(1):45—68.
7. Ro ss R. A thero sclero sis:A Defense M echanism Gone Aw ry-Am J Pathol, 1993,143(4):987～1002.
8. Reidy MA et al.Cireulation,1992;86(6):43—46.
9. M ajack RA, Goodman LV, and D ixit VM. Cell Surface Th rom-boaopondin Is Functionally Essential for Vasculor SmoothM us-cle Cell P ro liferation. J Cell Bio 1,1988,106(1):415～422.
10.M iano JM,V lasic N, To ta RR et al. Smoo thM uscle Cell Immediate-Early Gene and Grow th Factor A ctivation Follow vascu-lar Injury:A Putative In Vivo Mechanism fo r A utocrine Growth. A rteroscl Th romb,1993,13 (2):211～219.
11.L indner V, L app i DA, Baird A et al. Ro le of Basic Fibroblast Grow th Factor in Vascular Lesion Fo rmation. Circ Res,1991,68 (1):106～113.
12.J aw ien A, Bowen-Pope DE, L indner V et al. P latelet-derivedGrow th Facto r P romo tes Smoo th M uscle M igration and Inti-mal Th ickening in a RatModel of Balloon A ngiop lasty, J ClinInvest,1992,89 (2):507～511.
13.Sato Y, Hamanaka R, Ono J et al. The stimulato ry effect ofPDGF on vascular smoo th muscle cellm igration ismediated bythe induction of endogenous basic FGF. Biochem Biophys ResCommun,1991,174:1260～1226.
14.Jackson Cl, raines EW, Ross R et al. Ro le of EndogenousP latelet-derived Grow th Facto r in A rterial Smoo-th Muscle Cell Migration After Balloon Catheter Injury. A rtero scl Thromb,1993,13 (8):1218-1226.
15.Hwang DL, L atus LJ, and L ev-Ran A. Effects P latelet-Con-tained Grow th Facto r (PDGF, EGF, IGF-1, and TGF-B) on DNA Synthesis in Procine Aortic Smooth M uscle Cells in Culture. Exp Cell Res,1992,200:358～360.
16.KAWANO K, YOSH INO H, AOKI N, et al. Shear-inducedp latelet aggregation increases in patientswith p roximal and severe coronary artery stenosis[J]. Clin Cardiol,2002,25:154-160.
17.NEWBY A C. Dual role of matrix metallop roteinases (matrixins)in intimal thickening and atherosclerotic p laque rup ture [J].Physiol Rev,2005,85:1-31.
18.IBRAH IM A I, OBEID M T, JOUMA M J, et al. Detection ofherpes simp lex virus, cytomegalovirus and Ep stein-Barr virusDNA in atherosclerotic p laques and in unafected bypass grafts[J]. J Clin Virol,2005,32 (1):29-32.
19. GRYGLEWSKI R J, CHLOPICKI S J. Prostacyclin, nitric oxide and atherosclerosis[J]. Ann NYAcad SciUSA,1995,748:94-207.
20.JEREMY J Y, DASHWOOD M R. Microvascular repair [M]//Shep ro A M. Encyclopaedia of the microvasculature. New York:Elsevier Science,2006:903 911.
21.JEREMY J Y, BULBUL IA R, V IJAYAN V, et al. A bioabsor2bable (polyglactin) external sheath inhibits porcine saphenousvein graft thickening[J]. J Thorac Cardiovasc Surg,2004,127:1766-1772.
22.CARO C, JEREMY J Y, WATKINS N, et al. Geometry of un-stented and stented p ig common carotid artery bypass grafts[J]. JBiorheol,2002,39:507-512.
23.田晓东,高长青.血管外支撑防治移植静脉再狭窄的研究进展[J].中华综合临床医学杂志,2005,7：28-31.
24.Robin G,Smith M.Saphenous vein aorto-coronary artery bypass gafts with bete irradiation to Prevent graft oclusion.Artery,1997,22:278.
25.Ulus AT, TtlttoU, Zorlu F, prevention of intimal hyperplasia by single-dose pre-insertion external radiation in canine-vein in-terposition grafts.Eur J Vasc Endovase surg,2000,19:456
26.朱海龙,杨景学,张卫达,等低剂量日射线预防自体移植静脉内膜增生和狭窄的实验研究.中华实验外科杂志,2001,18：214.
27.Waugh J M, Kattash M, Li J, et al. Gene therapy to promote thromboresistance:local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. Proc Natl Acad Sci USA.1999;96(3):1065-1070.
28.Waugh J M, Yuksel E, Li J, et al. Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model. Circ Res.1999;84(1):84-92.
29.John D.Mannion MD.Michael L Saphenous vein graft protection:effects of c-myc antisense J Cardiovase Surg,1998,115:152
30.Michael J.Gary H.Robert S Genetic engineering of vein grafts resistant to atherosclerosis.Proc Natl Acad Sci USA,1995,92:4502
31.Bai H.Morishita R.Kida I.et al.(1998) Inhibition of intimal hyperplasia after vein grafting by in vivo transfer of human senescent cell-derived inhibitor-1 gene. Gene Ther 1998,5:761-769
32.George SJ, Baker AH, Angelini GD, Newby AC. Gene transfer of tissueinhibitor of
metalloproteinase inhibits metalloproteinase activity andneointima formation in human saphenous veins. Gene Ther.1998;5:1552-1560.
33.George SJ, Johnson JL, Angelini GD, Newby AC, Baker AH.Adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits SMC migration and neointima formation in human saphenous vein. Hum Gene Ther.1998;9:867-877.
34.Cable DG, O'Brien T, Schaff HV, Pompili VJ. Recombinant endothelial nitric oxide synthase-transduced human saphenous veins:gene therapy to augment nitric oxide production in bypass conduits. Circulation.1997;96(suppl Ⅱ):173-178.
35.Cable DG, Caccitolo JA, Pfeifer EA, Daly RC, Dearani JA, Mullany CJ,O'Brien T, Orszulak TA, Schaff HV. Endothelial regulation of vascular contractions in radial and internal mammary arteries. Ann Thorac Surg.1999;67:1083-1090.
36.徐斌,曹贵松,高瀚,等.腔内光动力疗法刘一血管吻合口内膜增生的抑制作用.第二军医大学学报,1999,20：857.
37.L icalzi L K, and Stansel HC. Failure of autogenous reversed saphenous vein femo ropop liteal grafting:pathophysio logy and prevention. Surgery,1982,91 (3):352～ 358.
38.Ro ss R. A thero sclero sis:A Defense M echanism Gone Awry.Am J Patho 1,1993, 143 (4):987～1002.
39.M ajack RA, Goodman LV, and D ixit VM. Cell Surface Throm-boaopondin Is Functionally Essential fo rV asculo r Smoo thM uscle Cell P ro liferation. J Cell Bio 1, 2008,106(1):415～422.
40.M iano JM,V lasic N, To ta RR et al. Smooth Muscle Cell Imme-Diate-Early Gene and Grow th Factor Activation Fo llow sV ascu-lar Injury:A Putative In V ivo M echanism fo r A utocrineGrow th. A rtero scl Th romb,1993,13 (2):211～219.
41.Dzau VJ, Gibbous GH, Ccooke JP et al. Vascular Biology andM edicine in the 1990s: Scope, Concep ts, Po tential, and Perspec-tives. Circulation,2003,87 (3):705～ 719.
42.Jawien A, Bowen-Pope DE, L indner V et al. P latelet-derived Growth Factor P romotes Smooth Muscle Migration and Inti-mal Thickening in a Rat Model of Balloon A ngiop lasty, J ClinInvest,2002,89 (2):507～511.
43.Sato Y, Hamanaka R, Ono J et al. The stimulatory effect of PDGF on vascular smooth muscle cell migration ismediated by the induction of endogenous basic FGF. Biochem Biophys ResCommun,2001,174:1260～1226.
44.Hwang DL, L atus LJ, and L ev2Ran A. Effects P latelet-Con-tained Grow th Factor (PDGF, EGF, IGF21, and TGF2B) on DNA Synthesis in Procine Aortic Smoo th Muscle Cells in Cul-
45.ture. Exp Cell Res,1992,200:358～360.
46.Ferns GAA, Stewart Lee AAL, and A nggard EE. A rterial response to mechanical injury:balloon catheter de2endo thelial-ization. A therosclero sis,1992,92 (1):89-104.
47.Dobin PB,L ittooy FN, and Endean ED. M echanical factors predisposing to intimal hyperp lasia and medial th ickening in auto-genous vein grafts. Surgery,1989,105 (3):393-400.
[2]. Ip JH, Fuster V. Syndromes of accelerated atherosclerosis:role of vascular injury and smooth muscle cell proliferation. Am Coll Cardiol.1990,15(7):1667-1687.
[3]. Chan AW, Chew DP, Lincoff AM. Update on pharmacology for restenosis.Curr Interv Cardiol Rep,2001,3:149-155.
[4]. Mintz GS, Weissman NJ, Teirstein PS, etal. Effect of intracoronary gamma-radiation therapy on in-stent restenosis:An intravascular ultrasound analysis from the GAMMA-lstudy.Circulation,2000,102:2915-2918.
[5]. Pugh CW,Ratcliffe PJ.Regulation of angiogenesis by hypoxia:role of the HIF systim[J].Nat Med,2003,9:677-684.
[6]. Mazure NM,Brahimi-Horn MC,Pouyssegur J.Proten kinases and thehypoxia-inducible factor-l,two switches in angiogenesis[J].Curr Pharm Des,2003,9:531-541.
[7].段小军,杨柳,周跃等.缺氧诱导因子促进血管生成的调控机制[J].中华创伤杂志,2004,20(8)：507-509.
[8]. Pugh CW,Ratcliffe PJ.Regulation of angiogenesis by hypoxia:role of the HIF system[J].Nat Med,2003,9:677-684.
[9]. Mazure NM,Brahimi-Horn MC,Pouyssegur J.Protein kinases and the hypoxia-inducible factor-l,two switches in angiogenesis[J].Curr Pharm Des,2003,9(7):531-541.
[10].6Hirot K.Hypoxia-inducible factor 1,a master transcription factor of cellular hypoxic gene expression[J].Anesth,2002,16:150-159.
[11]. Liu LX,Lu H,Luo Y,et al.Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1[J].Biochem Biophys Res Commun,2002,291:908-914.
[12]. 张勇,娄桂予,钱民章.建立兔高脂血症模型及动脉粥样硬化斑块的方法[J].遵义医学院报,2001,8,24：304
[13]. 郭延松,吴宗贵.鼠动脉粥样硬化模型复制方法的比较.中国动脉硬化杂志.2003,11(5)：465.
[14]. 李秋梅,王硕仁,赵明镜,等.家兔新型动脉粥样硬化狭窄模型的建立及其动态
观察[J].中国实验动物学报,2004,12(1)：26—28
[15]. Cottin Y, Kollum M,kolodgie FD, et al. Intravascular radiation accelerates atherosclerotic lesion formation of hyperc-holesterolemic rabbits[J]. Cardiovasc Radlat Med,2001,2(4):231—240
[16]. Plump AS, Smith JD. Severe hypereholes lerolemin and atheroselerosis in apolipoprotein E-deficient mice erealed by homologous recombination in ES cells. Cell, 1992.71,343
[17]. 张瑞华,余竹元,王卫群,等.肺炎衣原体感染与动脉粥样硬化动物模型研究新进展.海峡预防医学杂志,2002,8(3)：31—32.
[18]. Rubin EM. Isbids BY. Expression of human apolipoprotein A—1 in transgenic mice results in reduced plasma new high density lipoprotein size subclasses. Prec Nati Aead Sei USA.1991,353:265.
[19]. Ferrario CM.Use of angiotensin II receptor blockers in animal models of atherosclerosis. Am J Hypertens,2002,15(1 pt 2):9s—13s.
[20]. Varadi G, Mori Y, Mikala G, et al. Molecular determinations of Ca2+channel function and drug action.Trends Pharmacol Sci,1995,16(2):43-49.
[21]. Xie J, Guo Q, Zhu H, et al. Protein kinase C iota protects neural cells against apoptosis induced by amyloid beta-peptide.Brain Res Mol Brain Res,2000,82(1-2):107-113.
[22]. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Eng Med.1987;316(22):1371-1375.
[23]. Gibbons GH, Dzau V J. The Emerging Concept of Vascular Remodeling. N Eng Med.1994 330(20):1431—1438.
[24]. Tomasian D, Keaney. JF, Vite JA. Antioxidants and the bioaetivity of endothelitnn-derived nitric oxide. Cardivasc Res,2000,47(3):426-435
[25]. Dzau VJ, Gibbons GH, Mann M, Braun-Dullacus R. Future horizons in card-iovascul molecular therapeutics. Am Cardial,1997,80(9A):331—391
[26]. Lerman A, Cannon CR,Higano SH. et al Coronary vascular remodeling in asso-elation with endothelial dysfunction Am J Cardiol,1998.81:1105.1109
[27]. Tronc F, Wassef M, Esposito B. et al. Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol,1996,16:1256-1262.
[28]. Stein I,Itin A,Einat P,et al.Translation of vascular endothelial growth factor m RNA by inhternal ribosome entry:implications for translation under hypoxia[J].Mol Cell Bool,1998,18:3112-3119.
[29]. Gerber HP,Condorelli F,Park J,et al.Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes.Flt-l,but not Flk-1/KDR,is up-regulated by hypoxia[J].Biol Chem,1997,272:23659-23667.
[30]. Gassmann M,Chilov D,Wenger RH.Regulation of the hypoxia-inducible factor-1 alpha.ARNT is not necessary for hypoxic induction of HIF-1 alpha in the nucleus[J].Adv Exp Med Biol,2000,475:87-94.
[31]. Jiang BH,Zheng JZ,Leung SW,et al.Transactivation and inhibitory do mains of hypoxia inducible factor 1 alpha.Modulation of transcriptional activity byoxygen tension.[J]Biol Chem,1997,272;31:19253-19260.
[32]. Semenza GL.Hypoxia-inducible factor 1:control of oxygen homeostasis in health and disease[J].Pediatr Res,2001,49(5):614-617.
[33]. Richard DF, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the
[34]. induction of hypoxia2inducible factor-la in vascular smooth muscle cells. J Biol Chem,2000,275:26765-26771.
[35]. 杨镛,段志泉,张强,等.缺氧诱导因子21 α表达与移植静脉再内皮化关系的实验研究.中华医学杂志,2003,83：628-631.
[36]. Elson DA, Thurston G, Huang LE, et al. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing Hypoxia-inducible factor-la. Genes Dev,2001,15:2520-2532.
1. Gibbons GH, et al.The emerging concept of vascular remodeling N Engl J Med 1994; 330:1431-1438.
2. Nieolini FA, et al.Surg Clin NorthAm,1992;72(4):919—940.
3. Reidy MA et al.Atheroselerosis,1989;10(2):298—305.
4. Dilley RJ et al.Areh Surg,1988; 123(6):691—696.
5. Dilley RJ etal.Atherosclerosis1989;9(2):289—298.
6. Cox JL et al.Prog Cardilvasc Dis,1991;34(1):45—68.
7. Ro ss R. A thero sclero sis:A Defense M echanism Gone Aw ry-Am J Pathol, 1993,143(4):987～1002.
8. Reidy MA et al.Cireulation,1992;86(6):43—46.
9. M ajack RA, Goodman LV, and D ixit VM. Cell Surface Th rom-boaopondin Is Functionally Essential for Vasculor SmoothM us-cle Cell P ro liferation. J Cell Bio 1,1988,106(1):415～422.
10.M iano JM,V lasic N, To ta RR et al. Smoo thM uscle Cell Immediate-Early Gene and Grow th Factor A ctivation Follow vascu-lar Injury:A Putative In Vivo Mechanism fo r A utocrine Growth. A rteroscl Th romb,1993,13 (2):211～219.
11.L indner V, L app i DA, Baird A et al. Ro le of Basic Fibroblast Grow th Factor in Vascular Lesion Fo rmation. Circ Res,1991,68 (1):106～113.
12.J aw ien A, Bowen-Pope DE, L indner V et al. P latelet-derivedGrow th Facto r P romo tes Smoo th M uscle M igration and Inti-mal Th ickening in a RatModel of Balloon A ngiop lasty, J ClinInvest,1992,89 (2):507～511.
13.Sato Y, Hamanaka R, Ono J et al. The stimulato ry effect ofPDGF on vascular smoo th muscle cellm igration ismediated bythe induction of endogenous basic FGF. Biochem Biophys ResCommun,1991,174:1260～1226.
14.Jackson Cl, raines EW, Ross R et al. Ro le of EndogenousP latelet-derived Grow th Facto r in A rterial Smoo-th Muscle Cell Migration After Balloon Catheter Injury. A rtero scl Thromb,1993,13 (8):1218-1226.
15.Hwang DL, L atus LJ, and L ev-Ran A. Effects P latelet-Con-tained Grow th Facto r (PDGF, EGF, IGF-1, and TGF-B) on DNA Synthesis in Procine Aortic Smooth M uscle Cells in Culture. Exp Cell Res,1992,200:358～360.
16.KAWANO K, YOSH INO H, AOKI N, et al. Shear-inducedp latelet aggregation increases in patientswith p roximal and severe coronary artery stenosis[J]. Clin Cardiol,2002,25:154-160.
17.NEWBY A C. Dual role of matrix metallop roteinases (matrixins)in intimal thickening and atherosclerotic p laque rup ture [J].Physiol Rev,2005,85:1-31.
18.IBRAH IM A I, OBEID M T, JOUMA M J, et al. Detection ofherpes simp lex virus, cytomegalovirus and Ep stein-Barr virusDNA in atherosclerotic p laques and in unafected bypass grafts[J]. J Clin Virol,2005,32 (1):29-32.
19. GRYGLEWSKI R J, CHLOPICKI S J. Prostacyclin, nitric oxide and atherosclerosis[J]. Ann NYAcad SciUSA,1995,748:94-207.
20.JEREMY J Y, DASHWOOD M R. Microvascular repair [M]//Shep ro A M. Encyclopaedia of the microvasculature. New York:Elsevier Science,2006:903 911.
21.JEREMY J Y, BULBUL IA R, V IJAYAN V, et al. A bioabsor2bable (polyglactin) external sheath inhibits porcine saphenousvein graft thickening[J]. J Thorac Cardiovasc Surg,2004,127:1766-1772.
22.CARO C, JEREMY J Y, WATKINS N, et al. Geometry of un-stented and stented p ig common carotid artery bypass grafts[J]. JBiorheol,2002,39:507-512.
23.田晓东,高长青.血管外支撑防治移植静脉再狭窄的研究进展[J].中华综合临床医学杂志,2005,7：28-31.
24.Robin G,Smith M.Saphenous vein aorto-coronary artery bypass gafts with bete irradiation to Prevent graft oclusion.Artery,1997,22:278.
25.Ulus AT, TtlttoU, Zorlu F, prevention of intimal hyperplasia by single-dose pre-insertion external radiation in canine-vein in-terposition grafts.Eur J Vasc Endovase surg,2000,19:456
26.朱海龙,杨景学,张卫达,等低剂量日射线预防自体移植静脉内膜增生和狭窄的实验研究.中华实验外科杂志,2001,18：214.
27.Waugh J M, Kattash M, Li J, et al. Gene therapy to promote thromboresistance:local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model. Proc Natl Acad Sci USA.1999;96(3):1065-1070.
28.Waugh J M, Yuksel E, Li J, et al. Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model. Circ Res.1999;84(1):84-92.
29.John D.Mannion MD.Michael L Saphenous vein graft protection:effects of c-myc antisense J Cardiovase Surg,1998,115:152
30.Michael J.Gary H.Robert S Genetic engineering of vein grafts resistant to atherosclerosis.Proc Natl Acad Sci USA,1995,92:4502
31.Bai H.Morishita R.Kida I.et al.(1998) Inhibition of intimal hyperplasia after vein grafting by in vivo transfer of human senescent cell-derived inhibitor-1 gene. Gene Ther 1998,5:761-769
32.George SJ, Baker AH, Angelini GD, Newby AC. Gene transfer of tissueinhibitor of
metalloproteinase inhibits metalloproteinase activity andneointima formation in human saphenous veins. Gene Ther.1998;5:1552-1560.
33.George SJ, Johnson JL, Angelini GD, Newby AC, Baker AH.Adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits SMC migration and neointima formation in human saphenous vein. Hum Gene Ther.1998;9:867-877.
34.Cable DG, O'Brien T, Schaff HV, Pompili VJ. Recombinant endothelial nitric oxide synthase-transduced human saphenous veins:gene therapy to augment nitric oxide production in bypass conduits. Circulation.1997;96(suppl Ⅱ):173-178.
35.Cable DG, Caccitolo JA, Pfeifer EA, Daly RC, Dearani JA, Mullany CJ,O'Brien T, Orszulak TA, Schaff HV. Endothelial regulation of vascular contractions in radial and internal mammary arteries. Ann Thorac Surg.1999;67:1083-1090.
36.徐斌,曹贵松,高瀚,等.腔内光动力疗法刘一血管吻合口内膜增生的抑制作用.第二军医大学学报,1999,20：857.
37.L icalzi L K, and Stansel HC. Failure of autogenous reversed saphenous vein femo ropop liteal grafting:pathophysio logy and prevention. Surgery,1982,91 (3):352～ 358.
38.Ro ss R. A thero sclero sis:A Defense M echanism Gone Awry.Am J Patho 1,1993, 143 (4):987～1002.
39.M ajack RA, Goodman LV, and D ixit VM. Cell Surface Throm-boaopondin Is Functionally Essential fo rV asculo r Smoo thM uscle Cell P ro liferation. J Cell Bio 1, 2008,106(1):415～422.
40.M iano JM,V lasic N, To ta RR et al. Smooth Muscle Cell Imme-Diate-Early Gene and Grow th Factor Activation Fo llow sV ascu-lar Injury:A Putative In V ivo M echanism fo r A utocrineGrow th. A rtero scl Th romb,1993,13 (2):211～219.
41.Dzau VJ, Gibbous GH, Ccooke JP et al. Vascular Biology andM edicine in the 1990s: Scope, Concep ts, Po tential, and Perspec-tives. Circulation,2003,87 (3):705～ 719.
42.Jawien A, Bowen-Pope DE, L indner V et al. P latelet-derived Growth Factor P romotes Smooth Muscle Migration and Inti-mal Thickening in a Rat Model of Balloon A ngiop lasty, J ClinInvest,2002,89 (2):507～511.
43.Sato Y, Hamanaka R, Ono J et al. The stimulatory effect of PDGF on vascular smooth muscle cell migration ismediated by the induction of endogenous basic FGF. Biochem Biophys ResCommun,2001,174:1260～1226.
44.Hwang DL, L atus LJ, and L ev2Ran A. Effects P latelet-Con-tained Grow th Factor (PDGF, EGF, IGF21, and TGF2B) on DNA Synthesis in Procine Aortic Smoo th Muscle Cells in Cul-
45.ture. Exp Cell Res,1992,200:358～360.
46.Ferns GAA, Stewart Lee AAL, and A nggard EE. A rterial response to mechanical injury:balloon catheter de2endo thelial-ization. A therosclero sis,1992,92 (1):89-104.
47.Dobin PB,L ittooy FN, and Endean ED. M echanical factors predisposing to intimal hyperp lasia and medial th ickening in auto-genous vein grafts. Surgery,1989,105 (3):393-400.