VEGF-165基因对创伤性脑损伤保护作用的实验研究
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摘要
目的:血管内皮细胞生长因子( vascular endthelial growth factor ,VEGF)是一种存在于血管内皮细胞的特异性的促血管生长因子,对血管内皮细胞有强烈的促分裂、趋化作用和神经再生、修复作用。在脑缺血缺氧情况下,VEGF呈现表达上调。在创伤性脑损伤(traumatic brain injury ,TBI)的动物实验和临床研究中已发现VEGF的表达,认为TBI后VEGF的表达和上调与脑组织的自身保护有关[1-4]。本研究应用腺病毒(adenovirus, Ad)为载体的VEGF-165基因(Ad-VEGF-165)经损伤局部脑皮质处理创伤性脑损伤大鼠,观察脑挫裂伤周围组织在Ad-VEGF-165基因治疗后VEGF表达变化和CT灌注像及细胞凋亡之间的关系,研究外源性VEGF-165基因治疗TBI的可能性,探讨VEGF基因的脑保护作用,希望为颅脑创伤后的脑保护提供一些实验根据。
方法:
1.通过构建稳定表达的Ad- VEGF-165基因载体体系,并经损伤处脑皮质注入Ad- VEGF-165处理创伤性脑损伤大鼠,通过RT-PCR和Western blot检测脑伤后6 h、24 h、3 d、7 d、14 d VEGF-165在损伤局部的表达改变。
2.用激光共聚焦显微镜系统(laser scanning confocal microscopy,LSCM)和荧光双标技术动态检测Ad- VEGF-165基因治疗TBI后VEGF-165表达和细胞凋亡的改变,了解外源性VEGF基因治疗TBI与细胞凋亡的关系。
3.采用CT灌注像扫描(CT perfusion,CTP)动态检测Ad- VEGF-165基因治疗TBI前后损伤局部脑组织脑灌注的变化,观察外源性VEGF基因治疗与脑灌注的关系。
结果:
1.实验成功进行了携带重组腺病毒Ad-VEGF-165基因载体的构建、鉴定。外源性Ad-VEGF-165导入损伤局部脑组织后,VEGF在mRNA和蛋白质水平均有稳定的表达,并且其表达水平显著高于外伤组和质粒对照组。
2.激光共聚焦显微镜观察到创伤性脑损伤后VEGF表达上调,TBI+VEGF基因组VEGF表达更为明显;TBI+VEGF基因组的细胞凋亡在伤后2 4h、3 d、7 d与TBI组比较有显著的减少,细胞凋亡与VEGF的关系密切。
3.CT灌注像显示创伤后1 h损伤局部有明显的(cerebral blood flow, CBF)、脑血容量(cerebral blood volume ,CBV)降低。伤后24 h CBF、CBV开始增高,伤后3d时达到高峰。伤后14d CBV基本恢复正常。TBI+VEGF组伤后3d、7d和14d脑灌注明显高于TBI组。
结论:VEGF与创伤性脑损伤关系密切。研究表明,不仅在损伤后随着时间的不同VEGF表达发生动态的改变,而且Ad-VEGF-165基因对于创伤性脑损伤后局部脑灌注有一定改善,并对减轻脑损伤组织细胞凋亡有一定的作用。从而证实了外源性的VEGF基因治疗对于创伤性脑损伤的有效性,为基因治疗脑外伤的临床应用的可能提供了一定的实验基础。
Objective: Vascular endthelial growth factor (VEGF), produced by vascular endothelial cells, has been recognized as a one of the most important factor with angiogenesis, neuroprotection and nerve regeneration. Hypoxic in brain tissue due to traumatic brain injury (TBI) will induce the increased expression of VEGF. Researchers pointed out that the upgrade of VEGF expression on the experimental and clinical researches was evidenced the relationship between the VEGF and the neuroprotection. The present study was to investigate the expression level of VEGF in TBI on rat following a treatment of Ad-VEGF-165 gene applied to the injury sector using laser scanning confocal microscopy (LSCM), RT-PCR and Western blot, and the relationship between the expression level and the apoptosis, CT perfusion (CTP). This study provides both rationale and experiment evidences for neuroprotection after TBI using Ad-VEGF-165 gene.
Materials and Methods:
1. A recombinant adenoviral (rAd) vector carrying VEGF-165 which can be used for gene therapy in TBI was constructed, and its expression in vitro and in vivo was researched. There was an increased expression of VEGF in different time after a gene treatment by injected to the cortex of injury sector.
The expression level of VEGF and apoptosis after TBI following a treatment of Ad-VEGF-165 gene was detected by immunofluorescence using LSCM.
3. The dynamic CT perfusion imaging were obtained in different time on pre- and post-therapy of Ad-VEGF-165 gene to observe the changes of cerebral perfusion.
Results:
1. Ad-VEGF-165 gene was constructed successfully by recombinant techenic. RT-PCR and Western blot shows that the expression of VEGF mRNA and protein has been increased in injury sector after TBI with gene thearyp.
2. A decreased apoptosis with increased VEGF expression observed by LSCM remarkably on 24h, 3d, 7d after TBI following an Ad-VEGF-165 gene therapy, and showed a close relationship between apoptosis and VEGF.
3. The cerebral perfusion on CT perfusion imaging after TBI represents a lower CBF and CBV in early stage, and higher in 24h, 3d, 7d which indicates a hyperperfusion due to unsound hemodynamics after TBI. An improved cerebral perfusion was significant for TBI with gene therapy to build collateral circulation.
Conclusions: VEGF expression in the TBI could be great associated with neuroprotection following brain harm due to hypoxia, and applying Ad-VEGF-165 to the cerebral cortex in injury sector would be an exercisable method to improve cerebral perfusion and come down apoptosis. This research provides both rationale and experiment evidences for designing high effectiveness way to the gene treatment of TBI. It lays foundation for the research on clinical application of angiogenic gene therapy of TBI.
方法:
1.通过构建稳定表达的Ad- VEGF-165基因载体体系,并经损伤处脑皮质注入Ad- VEGF-165处理创伤性脑损伤大鼠,通过RT-PCR和Western blot检测脑伤后6 h、24 h、3 d、7 d、14 d VEGF-165在损伤局部的表达改变。
2.用激光共聚焦显微镜系统(laser scanning confocal microscopy,LSCM)和荧光双标技术动态检测Ad- VEGF-165基因治疗TBI后VEGF-165表达和细胞凋亡的改变,了解外源性VEGF基因治疗TBI与细胞凋亡的关系。
3.采用CT灌注像扫描(CT perfusion,CTP)动态检测Ad- VEGF-165基因治疗TBI前后损伤局部脑组织脑灌注的变化,观察外源性VEGF基因治疗与脑灌注的关系。
结果:
1.实验成功进行了携带重组腺病毒Ad-VEGF-165基因载体的构建、鉴定。外源性Ad-VEGF-165导入损伤局部脑组织后,VEGF在mRNA和蛋白质水平均有稳定的表达,并且其表达水平显著高于外伤组和质粒对照组。
2.激光共聚焦显微镜观察到创伤性脑损伤后VEGF表达上调,TBI+VEGF基因组VEGF表达更为明显;TBI+VEGF基因组的细胞凋亡在伤后2 4h、3 d、7 d与TBI组比较有显著的减少,细胞凋亡与VEGF的关系密切。
3.CT灌注像显示创伤后1 h损伤局部有明显的(cerebral blood flow, CBF)、脑血容量(cerebral blood volume ,CBV)降低。伤后24 h CBF、CBV开始增高,伤后3d时达到高峰。伤后14d CBV基本恢复正常。TBI+VEGF组伤后3d、7d和14d脑灌注明显高于TBI组。
结论:VEGF与创伤性脑损伤关系密切。研究表明,不仅在损伤后随着时间的不同VEGF表达发生动态的改变,而且Ad-VEGF-165基因对于创伤性脑损伤后局部脑灌注有一定改善,并对减轻脑损伤组织细胞凋亡有一定的作用。从而证实了外源性的VEGF基因治疗对于创伤性脑损伤的有效性,为基因治疗脑外伤的临床应用的可能提供了一定的实验基础。
Objective: Vascular endthelial growth factor (VEGF), produced by vascular endothelial cells, has been recognized as a one of the most important factor with angiogenesis, neuroprotection and nerve regeneration. Hypoxic in brain tissue due to traumatic brain injury (TBI) will induce the increased expression of VEGF. Researchers pointed out that the upgrade of VEGF expression on the experimental and clinical researches was evidenced the relationship between the VEGF and the neuroprotection. The present study was to investigate the expression level of VEGF in TBI on rat following a treatment of Ad-VEGF-165 gene applied to the injury sector using laser scanning confocal microscopy (LSCM), RT-PCR and Western blot, and the relationship between the expression level and the apoptosis, CT perfusion (CTP). This study provides both rationale and experiment evidences for neuroprotection after TBI using Ad-VEGF-165 gene.
Materials and Methods:
1. A recombinant adenoviral (rAd) vector carrying VEGF-165 which can be used for gene therapy in TBI was constructed, and its expression in vitro and in vivo was researched. There was an increased expression of VEGF in different time after a gene treatment by injected to the cortex of injury sector.
The expression level of VEGF and apoptosis after TBI following a treatment of Ad-VEGF-165 gene was detected by immunofluorescence using LSCM.
3. The dynamic CT perfusion imaging were obtained in different time on pre- and post-therapy of Ad-VEGF-165 gene to observe the changes of cerebral perfusion.
Results:
1. Ad-VEGF-165 gene was constructed successfully by recombinant techenic. RT-PCR and Western blot shows that the expression of VEGF mRNA and protein has been increased in injury sector after TBI with gene thearyp.
2. A decreased apoptosis with increased VEGF expression observed by LSCM remarkably on 24h, 3d, 7d after TBI following an Ad-VEGF-165 gene therapy, and showed a close relationship between apoptosis and VEGF.
3. The cerebral perfusion on CT perfusion imaging after TBI represents a lower CBF and CBV in early stage, and higher in 24h, 3d, 7d which indicates a hyperperfusion due to unsound hemodynamics after TBI. An improved cerebral perfusion was significant for TBI with gene therapy to build collateral circulation.
Conclusions: VEGF expression in the TBI could be great associated with neuroprotection following brain harm due to hypoxia, and applying Ad-VEGF-165 to the cerebral cortex in injury sector would be an exercisable method to improve cerebral perfusion and come down apoptosis. This research provides both rationale and experiment evidences for designing high effectiveness way to the gene treatment of TBI. It lays foundation for the research on clinical application of angiogenic gene therapy of TBI.
引文
[1] NIssen NN, Polverini PJ, Koch AE, et al, Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing [J] Am J Pathol, 1998, 152(6): 1445-1452.
[2] Chow J, Ogunshola O Fan SY ea al, Astrocyte-derived VEGF mediates survival and tube stabilization of hypoxic brain microvascular endothelial cells in vitro. Brain Res Dev Brain Res. 2001 Sep 23; 130(1): 123-32.
[3] Papavassiliou E, Gogate N, Proescholdt M, et al. Vascular endothelial brain. J Neurosci Res, 1997, 49:451-460.
[4] 吴雪海,高亮,亚平等.闭合性颅脑损伤血浆血管内皮细胞生长因子的变化和意义[J]中国急诊医学杂志, 2003 Dec 12; 830-832
[5] Sun Y, Jin K, Xie L, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia[J]. J Clin Invest. 2003,111(12): 1843-51.
[6] Isner JM, Takayuki A .Therapeutic angiogenesis. Front-Biosci. 1998 May 5; 3: e49-69
[7] Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures [J]. Neuroscience, 1999, 90(4): 1529-41.
[8] Rovak JM, Mungara AK, Aydin MA, et al. Effects of vascular endothelial growth factor on nerve regeneration in a cellular nerve grafts [J]. Reconstr Microsurg, 2004, 20(1): 53-8.
[9] Christenson SD, Lake KD, Ooboshi H, et al. Adenovirus-mediated gene transfer in vivo cerebral blood vessels and perivascular tissue in mice [J]. Stroke, 1998, 29(7): 1411-1415.
[10] 饶宜光,褚晓凡,付学军等.不同途径导入 rAAV-VEGF165 基因对大鼠脑缺血边缘区血管生成的影响[J].中风与神经疾病杂志, 2006, 23(2):217-219.
[11] Kusaka N,Sugiu K,Tokunaga K,et al. Enhanced brain angiogenesis in chronic cerebral hypoperfusion after administration of plasmid human vascular endothelial growth factor in combination with indirect vasoreconstructive surgery[J]. J Neurosurg, 2005, 103(5): 882-90.
[1] 韩久卉,张英泽.中枢神经系统对腺病毒载体的免疫应答[J].中华微生物学和免疫学杂志,2006,26(9):863-866。
[2] Araki K, Shiotani A, Watabe K, et al. Adenoviral GDNF gene transfer enhances neurofunctional recovery after recurrent laryngeal nerve injury [J]. Gene Ther, 2006; 13(4): 296-303.
[3] Doi K, Nibu K, Ishida H, Okado H, et al. Adenovirus-mediated gene transfer in olfactory epithelium and olfactory bulb: a long-term study [J]. Ann Otol Rhinol Laryngol ,2005; 114(8): 629-633.
[4] Gauthier R, Joly S, Pernet V, et al. Partial correction of sensitivity to oxidant stress in Friedreich ataxia patient fibroblasts by frataxin-encoding adeno-associated virus and lentivirus vectors [J]. Hum Gene Ther, 2005; 16(8): 947-956
[5] 石忠松,黄正松,郭少雷等.重组腺病毒载体介导外源基因转移至痉挛脑血管的研究[J].中华实验外科杂志,2004,21(10):1239-1240.
[6] 吴伟.重组腺病毒载体转导的脑源性神经生长因子在大鼠体外培养海马神经元谷氨酸损伤模型中的保护作用[J].中华神经科杂志 2005,38(7 ):457-459
[1] Perri B R, Smith D H, Murai H, et al. Metabolic quantification of lesion volume following experimental traumatic brain injury in the rat[J]. J Neurotrauma,1997,114(1):15-22.
[2] Dixon CE, Lyeth BG, Povlishock JT,et al. A fluid percussion model of experimental brain injury in the rat[J]. J Neurosurg,1987,67(1):110-119.
[3] 李力仙,王天佑,钟震宇等.自由落体和液压致大鼠脑损伤的对比研究.中华实验外科杂志,1999,16(5):447-448。
[4] Sullivan HG, Martinez J, Becker DP, et al. Fluid-percussion model of mechanical brain injury in the cat[J]. J Neurosurg.1976;45:520-534.
[5] Feeney DM,Boyeson MG,Linn RT,et al. Methodology and local effects of contusion in the rat[J].Brain Res.1981;211(1):67-77
[6] 王国强,廖维宏,李芳等.创伤性脑损伤诱导海马细胞凋亡模型的建立[J].第三军医大学学报,2000,Vol.22 No.9,P.826-830.
[7] Yano A, Shingo T, Takeuchi A,et al. Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia[J]. J Neurosurg. 2005, 103(1): 104-14.
[8] Rosenstein JM, Mani N, Sliverman WF, et al. Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and vivo[J]. Proc Natl Acad Sci USA, 1998, 95(12): 7086-91.
[9] 孟云,陈吉相,孙圣刚.脑室注射 VEGF-165 对实验性脑出血大鼠血脑屏障的影响[J].卒中与神经疾病,2006,13(2):79-81.
[10] Christenson SD, Lake KD, Ooboshi H, et al. Adenovirus-mediated gene transfer in vivo cerebral blood vessels and perivascular tissue in mice [J]. Stroke, 1998, 29(7):1411-1415.
[11] 饶宜光,褚晓凡,付学军等.不同途径导入 rAAV-VEGF165 基因对大鼠脑缺血边缘区血管生成的影响[J].中风与神经疾病杂志,2006,23(2):217-219.
[12] 徐忠铧,唐文渊,朱晓峰.转基因干细胞移植对脑外伤大鼠的保护作用[J].中国急救医学,2006,(26)7,515-517.
[1] 蒲传强,郎森阳,吴卫平,编著.脑血管病学.北京:人民军医出版社,1999:141-145
[2] 邓平,徐小虎,陈耀文等.激光扫描共聚焦显微镜观察脑干中的神经轴突[J].中华物理学杂志,2000,22(1):23-24.
[3] Smith FM, Horsburgh K, Nicoll JAR, et al. TUNEL staining of contusions after fatal head injury in man [J]. Neurotrauma, 1998, 15:54-59.
[4] Ng I, Yeo TT, Tang WY, et al. Apoptosis occurs after cerebral contusion in humans [J]. Neurosurgery, 2000,46(4): 949-956.
[5] 王国强,廖维宏,李芳等.创伤性脑损伤诱导海马细胞凋亡模型的建立[J].第三军医大学学报,2000,(22)9:826-830.
[6] Montal M. Mitochondria, glutamate neurotoxicity and the death cascade[J]. Biochim Biophys Acta,1998,1 366(1-2):113-126.
[7] Kitamura Y, Ota T, Matsuoka Y, et al. Hydrogen peroxide-induced apoptosis mediated by p53 protein in glial cells[J]. Glia, 1999, 25(2): 154-164.
[8] Levick Y, Coffey HD, Mello SR. opposing effects of thapsigargin at survival of developing cerebrallar granule neurons in culture [J]. Brain Res, 1995,676(2): 325-335.
[9] Pizzi M, Coffi F, Boroni F, et al. opposing roles for NF-KB reflector P65 and c-Rel in the modulation of neuron survival elicited by glutamate and interleukin-1 beta [J].Biol Cherm,2002,277(28):20717-20723.
[10] Iwasaki Y, Ikeda K. Prevention by insulin-like growth factor-1 and rilozole in motor neuron death after neonatal axotomay[J].Neurol Sci,1999,169:148-155.
[11] 周乐,师蔚,孙建军等.亚低温对脑外伤后细胞调亡影响[J].西安交通大学学报(医学版),2003,24(4):342-344.
[12] Jin KL, Mao XO, Greenberg DA, et al. Vascular endothelial growth factor: director neuroprotective effect in vitro ischemia [J]. PNAS, 2000,97(18): 10 242-10 247
[13] 陈兴洲,陆立勋.血管内皮细胞生长因子与脑缺血[J].国外医学:脑血管疾病分册, 1997,(5):259-262.
[14] Alon T, Hemo I, Itin A, et al. Vascular endothelial growth factor acts as a survival factor for newlyformed retinal vessels and has implication for fretinopathy ofprematrurity[J]. Nat Med, 1995,1:1 024-1 028
[15] Jin KL, Mao XO, Greenberg DA. Vascular endothelial growth factor: direct neuroprotective effect in vitro ischemia [J]. Proc Natl Acad Sci U S A.2000, 29,97(18): 10242-7.
[16] Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures [J]. Neuroscience, 1999, 90(4): 1529-41.
[17] Zhang QK, Magovern CJ, Mack CA, et al. Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediated angiogenesis [J]. J Surg Res, 1997, 67(3): 147-154.
[18] Sk?ld MK, Risling M, Holmin S. Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration [J].Eur J Neurosci,2006, 23(1): 21-34.
[1] Wintermark M, Chiolero R, Van Melle G, et al. Cerebral vascular autoregulation assessed by perfusion-CT in severe head trauma patients[J]. J Neuroradiol, 2006, 33(1):27-37.
[2] Dohmen C, Bosche B, Graf R, et al. Identification and clinical impact of impaired cerebrovascular autoregulation in patients with malignant middle cerebral artery infarction[J]. Stroke, 2007, 38(1):56-61.
[3] Wintermark M, van Melle G, Schnyder P, et al. Admission perfusion CT: prognostic value in patients with severe head trauma [J]. Radiology, 2004, 232(1):211-20.
[4] Wintermark M, Chioléro R, van Melle G, et al. Relationship between brain perfusion computed tomography variables and cerebral perfusion pressure in severe head trauma patients[J]. Crit Care Med, 2004, 32(7):1579-87.
[5] Wintermark M, Cotting J, Roulet E, et al. Acute brain perfusion disorders in children assessed by quantitative perfusion computed tomography in the emergency setting[J]. Pediatr Emerg Care, 2005, 21(3):149-60.
[6] 王 忠 诚 , 主 编 . 王 忠 诚 神 经 外 科 学 . 第 一 版 , 湖 北 , 湖 北 科 学 技 术 出 版社,2005:370-371.
[7] K.A. Miles. Brain perfusion: computed tomography applications [J].Neuroradiology, 2004, 46(s): 194–200.
[8] Harada JN, Lee LY, Patel SR, et al. Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor[J].Ann Thorac Surg,2000.69(1):14
[9] 蒋国顺,朱朗标,高长青等.VEGF165cDNA 治疗缺血性心肌后心肌灌注和代谢的变化[J].解放军医学杂志,2002,27(3):217-218.
[10] 武柏林,刘怀军,汪国石等.MR 灌注成像对 VEGF 质粒治疗犬脑梗塞效果评价的实验研究[J].中国临床医学影像杂志,2003,14(5):310-315.
[11] Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures[J]. Neuroscience, 1999, 90(4): 1529-41.
[12] Rosenstein JM, Mani N, Sliverman WF, et al. Patterns of brain angiogenesis aftervascular endothelial growth factor administration in vitro and vivo[J]. Proc Natl Acad Sci USA, 1998, 95(12):7086-91.
[13] Christenson SD, Lake KD, Ooboshi H, et al. Adenovirus-mediated gene transfer in vivo cerebral blood vessels and perivascular tissue in mice [J]. Stroke, 1998, 29(7):1411-1415.
[14] 饶宜光,褚晓凡,付学军等.不同途径导入 rAAV-VEGF165 基因对大鼠脑缺血边缘区血管生成的影响[J].中风与神经疾病杂志,2006,23(2):217-219.
[1] Infanger M, Schmidt O, Kossmehl P, et al. Vascular endothelial growth factor serum level is strongly enhanced after burn injury and correlated with local and general tissue edema [J].Burn, 2004,30(4):305-311.
[2] Corral CJ, Siddiqui A, Wu L, et al. Vascular endothelial growth factor is important than basic fibroblastic growth factor during ischemic wound healing [J]. Arch surg, 1999, 134(2):200-205.
[3] Pilch H, Schlenger K, Steiner E, et al. Hypoxia-stimulated expression of angiogenic growth factors in cervical cancer cell and cervical cancer-drivered fibroblasts[J]. Int J Gynecal Cancer, 2001, 11(2):137-142.
[4] 史福平,王珊,张国华.血管内皮细胞生长因子在脑血管病中的研究进展.综述[J]. 临床神经病学杂志,2006,19(3).234-236.
[5] Zhang QK, Magovern CJ, Mack CA, et al. Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediatedangiogenesis[J]. J Surg Res, 1997, 67(3):147-154.
[6] Rovak JM, Mungara AK, Aydin MA, et al. Effects of vascular endothelial growth factor on nerve regeneration in a cellular nerve grafts[J]. J Reconstr Microsurg, 2004, 20(1): 53-8.
[7] Facchiano F, Fernandez E, Mancarella S, et al. Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor[J]. J Neurosurg, 2002, 97(1): 161-8.
[8] Jin K,Zhu Y,Sun Y, et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo[J]. Proc-Natl-Acad-Sci-U-S-A, 2002, 99(18): 11946-50.
[9] Jin K, Mao XO, Greenberg DA,et al. Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling[J]. J Neurobiol, 2006, 66(3):236-42.
[10] Kovacs Z, Ikezaki K, Samoto K, et al. VEGF and flt. Expression time kinetics in rat brain infarct[J]. Stroke, 1996, 27(10): 1865-72.
[11] Issa R, Krupinski J, Bujny T, et al. Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke[J]. Lab-Invest, 1999, 79(4): 417-25.
[12] 张爱梅,李宪章,靳光娴等.缺血性血管病患者血清 VEGF 和 IL-1β的变化及意义[J].临床神经病学杂志,2002,15(6):341-343.
[13] NIssen NN, Polverini PJ, Koch AE, et al, Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing[J]. Am J Pathol, 1998, 152(6):1445-1452.
[14] Chow J, Ogunshola O Fan SY ea al, Astrocyte-derived VEGF mediates survival and tube stabilization of hypoxic brain microvascular endothelial cells in vitro[J]. Brain Res Dev Brain Res, 2001, 130(1): 123-32.
[15] Papavassiliou E, Gogate N, Proescholdt M, et al. Vascular endothelial growth factor(vascular permeability factor) expression in injuried rat brain[J]. J Neurosci Res, 1997, 49:451-460.
[16] 吴雪海,高亮,金亚平等.闭合性颅脑损伤血浆血管内皮细胞生长因子的变化和意义[J].中国急诊医学杂志,2003 Dec 12: 830-832.
[17] 吴克荣,催建华,顾玉林等.大鼠冲击损伤后 VEGF 的表达与损伤后存活时间关系的实验研究[J].南通大学学报,2006,26(2):85-87.
[18] 吕文,陈建良,杨地等.bFGF、VEGF 在大鼠创伤脑组织中的表达及关系[J].中风与神经疾病杂志, 2004,21(1):33-35.
[19] Sk?ld MK, von Gertten C, Sandberg-Nordqvist AC, et al. VEGF and VEGF receptor expression after experimental brain contusion in rat[J]. J Neurotrauma, 2005, 2(3):353-67.
[20] Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures[J]. Neuroscience, 1999, 90(4): 1529-41.
[21] Rovak JM, Mungara AK, Aydin MA,et al. Effects of vascular endothelial growth factor on nerve regeneration in acellular nerve grafts[J]. J Reconstr Microsurg, 2004, 20(1): 53-8.
[22] Hayashi T, Abe K, Itoyama Y. Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia[J]. J Cereb Blood Flow Metab, 1998, 18(8): 887-95.
[23] Zhang ZG, Zhang L, Tsang W, et al. Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after foca cerebral ischemia[J]. J Cerebral Blood Flow Metab, 2002, 22(4):379-392.
[24] Nag S, Eskandarian MR, Davis J, et al. Differential expression of vascular endothelial growth factor-A (VEGF-A) and VEGF-B after brain injury[J]. J Neuropathol Exp Neurol, 2002, 61(9): 778-88.
[25] Yano A, Shingo T, Takeuchi A, et al. Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia[J]. J Neurosurg, 2005 , 103(1): 104-14.
[26] Rosenstein JM, Mani N, Sliverman WF, et al. Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and vivo[J]. Proc Natl Acad Sci USA, 1998, 95(12):7086-91.
[27] 孟云,陈吉相,孙圣刚.脑室注射 VEGF-165 对实验性脑出血大鼠血脑屏障的影响[J].卒中与神经疾病,2006,13(2):79-81.
[28] Christenson SD, Lake KD, Ooboshi H, et al. Adenovirus-mediated gene transfer in vivo cerebral blood vessels and perivascular tissue in mice [J]. Stroke, 1998,29(7):1411-1415.
[29] 饶宜光,褚晓凡,付学军等.不同途径导入 rAAV-VEGF165 基因对大鼠脑缺血边缘区血管生成的影响[J].中风与神经疾病杂志,2006, 23(2):217-219.
[30] Kusaka N,Sugiu K,Tokunaga K,et al. Enhanced brain angiogenesis in chronic cerebral hypoperfusion after administration of plasmid human vascular endothelial growth factor in combination with indirect vasoreconstructive surgery[J]. J Neurosurg, 2005, 103(5): 882-90.
[31] van Bruggen N, Thibodeaux H, Palmer JT, et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain[J]. J Clin Invest, 1999, 104(11):1613-20.
[32] Sk?ld MK, Risling M, Holmin S. Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration[J]. Eur J Neurosci, 2006, 23(1):21-34.
[1] Miles KA, Hayball MP, Dixon AK. Color perfusion imaging: a new application of computed tomography[J]. Lancet, 1991, 337(3): 643-645.
[2] Miles KA. Measurement of tissue perfusion by dynamic computed tomography [J]. Br J Radiol,1991,64(761): 409-412.
[3] K.A. Miles. Brain perfusion: computed tomography applications [J]. Neuroradiology, 2004,46(s): 194–200.
[4] Nabavi DG, Cenic A, Craen RA, et al. CT assessment of cerebral perfusion: experimental validation and initial clinical experience[J]. Radiology,1999,213(1): 141-149.
[5] Eastwood JD, Lev MH, Azhari T, et al. CT perfusion scanning with deconvolution analysis: pilot study in patients with acute middle cerebral artery stroke [J]. Radiology, 2002, 222(1): 227-236.
[6] Lawrence KS, Lee TY .An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: II. Experimental validation [J].J-Cereb-Blood-Flow-Metab, 1998 ,18(12): 1378-85.
[7] Lawrence KS, Lee TY. An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: I. Theoretical derivation[J].J-Cereb-Blood-Flow-Metab, 1998 ,18(12): 1365-77.
[8] 刘翔,戴建平,孙波等.CT 灌注成像在脑内缺血性疾病中的初步应用[J].中华放射学杂志,1999,33: 452-455.
[9] Koenig M, Klotz E, Luda B, et al. Perfusion CT of the brain: diagnostic approach for early detection of ischemic stroke [J]. Radiology, 1998, 209:85-93.
[10] 张红梅,高培毅,胡平英.脑组织血流灌注的动态 CT 定量研究[J].中华放射学杂志,1999,33:448-451.
[11] Koenig M, Dphil EK, Luda B, et al. Perfusion CT of the brain: new diagnostic approach for early detection of ischemic stroke [J]. Radiology, 1996, 201:236.
[12] Gillard JH, Bearcroft PW, Miles KA. et, al. Evaluation of quantitative cerebral CT perfusion with positron emission tomography: preliminary results [J]. Radiology, 1997, 205:185.
[13] Klotz E, Koeng M. Perfusion measurements of the brain: using dynamic CT for the qantitative assessment of cerebral ischemia in acute stroke [J]. Eur J Radiol, 1999, 30:170-184.
[14] Kloska SP, Fischer T, Nabavi DG, et, al. Comparison of Different Iodine Concentration Contrast Media in Perfusion Computed Tomography of the Brain: Is High Iodine Concentration Useful? [J]. Invest Radiol, 2007 ,42(8):564-8.
[15] Wintermark M., Lepori D, Cotting J, et al. Brain Perfusion in Children: Evolution With Age Assessed by Quantitative Perfusion Computed Tomography [J]. Pediatrics,2004 ,113 (6) :1642-52.
[16] Reichenbach JR, Rother J, Jonetz-Mentzel, et al. Acute stroke evaluated by time-to-peak mapping during initial and early follow-up perfusion CT studies [J]. AJNR, 1999, 20:1842-1850.
[17] Gobbel CT, Cann CE, Fike JR. Comparison of xenon-enhanced CT with ultrafast CT for measurement regional cerebral blood flow [J]. AJNR, 1993, 14:543-550.
[18] Wirestam R, Ryding E, Lindgren A, et al. Regional cerebral blood flow distributions in normal volrnteers: dynamic susceptibility contrast MRI compared with 99m Tc-HMPAO-SPECT [J]. J Comput Assist Tomogr, 2000, 24:526-530.
[19] Hunter GJ, Hamberg LM, Ponzo JA, et al. Assessment of cerebral perfusion and arterial anatomy in hyperacute stroke with three-dimensional functional CT: early clinical results [J]. AJNR, 1998, 19:29-37.
[20] Hamberg LM, Hunter GJ, Kierstead D, et al. Measruement of quantitative CBV with subtraction three-dimensional functional CT [J]. AJNR, 1996, 17:1961-1869.
[21] Shih TTF, Huang KM. Acute stroke: detection of changes in cerebral Perfusion with dynamic CT scanning [J]. Radiology, 1988, 169:469-174.
[22] Scharf J, Brockmann MA, Daffertshofer M, et al. Improvement of Sensitivity and Interrater Reliability to Detect Acute Stroke by Dynamic Perfusion Computed Tomography and Computed Tomography Angiography[J] .J Comput Assist Tomogr, 2006 ,30(1):105-10.
[23] 周丽红,王嗣欣,赵亮等.症状性颅内外动脉狭窄内支架成型术前后脑灌注 CT 成像的变化及与临床疗效的关系[J].中国神经精神疾病杂志,2007,(33)1,51-53
[24] Wintermark M. Relationship between brain perfusion computed tomography variables and cerebral perfusion pressure in severe head trauma patients[J]. Crit Care Med,2004,32(7):1621-3.
[25] Wintermark M, van Melle G, Schnyder P. et, al. Admission perfusion CT: prognostic value in patients with severe head trauma[J]. Radiology, 2004, 232(1): 211-220.
[26] Wintermark M, Chiolero R, Van Melle G, et al. Cerebral vascular autoregulation assessed by perfusion-CT in severe head trauma patients[J]. J Neuroradiol, 2006, 33(1): 27-37
[27] Wintermark M, van Melle G, Schnyder P, et al. Prognostic value of admission perfusion-CT in severe head trauma patients[J]. Radiology, 2004, 232:211-220.
[28] Qureshi AI, Kirmani JF, Xavier AR, et al. Computed tomographic angiography for diagnosis of brain death[J]. Neurology, 2004, 62(4):652-3.
[29] Hemphill JC, Smith WS, Sonne DC, et al. Relationship between brain tissue oxygen tension and CT perfusion: feasibility and initial results [ J ] . AJNR-Am-J-Neuroradiol, 2005, 26(5): 1095-100.
[30] Charles B. L. M. Majoie, Leonard J. van Boven, Diederik van de Beek, et, al. Perfusion CT to Evaluate the Effect of Transluminal Angioplasty on CerebralPerfusion in the Treatment of Vasospasm After Subarachnoid Hemorrhage[J]. Neurocrit Care, 2007, 06:40–44.
[31] 于涛,王中,周岱等.应用CT灌注成像研究兔蛛网膜下腔出血后脑血流的变化[J].江苏医药,2005(31)9,683-685.
[32] Sviri, Gill E. Dynamic Perfusion Computed Tomography in the Diagnosis of Cerebral Vasospasm[J]. Neurosurgery, 2006, 59(2): 319-325
[33] Turowski B, Haenggi D, Wittsack J, et al. Cerebral perfusion computerized tomography in vasospasm after subarachnoid hemorrhage: diagnostic value of MTT[J]. Rofo, 2007, 179(8): 847-54.
[34] Pham M, Johnson A., Bartsch AJ, et, al. CT perfusion predicts secondary cerebral infarction after aneurysmal subarachnoid hemorrhage[J ].Neurology, 2007, 69:762-765
[35] 丁陪,凌华威,张欢等.胶质瘤 CT 灌注成像对脑血容量与血管表面通透性的相关研究[J].中华放射学杂志 2007,(41)1: 25-28
[36] Lev MH, Ozsunar Y, Henson JW, et al. Glial tumor grading and outcome prediction using dynamic spin-echo MR susceptibility mapping compared with conventional contrast-enhanced MR: confounding effect of elevated rCBV of oligodendrogliomas[J]. AJNR, 2004, 25:214-221.
[37] Yeung WT, Lee TY, Del Maestro RF, et al. Effect of steroids on iopamidol blood-brain transfer constant and plasma volume in brain tumors measured with X-ray computed tomography[J]. J Neurooncol, 1994, 18:53–60.
[38] Bondestam S, Halavaara J T., Jaaskelainen J E. Perfusion CT of the Brain in the Assessment of Flow Alterations during Brachytherapy of Meningioma[J]. Acta Radiologica, 1999, 40(5): 469-473.
[39] Leggett DA, Miles KA, Kelley BB. Blood-brain barrier and blood volume imaging of cerebral glioma using functional CT: a pictorial review[J].Australas Radiol, 1998, 42:335-340.
[2] Chow J, Ogunshola O Fan SY ea al, Astrocyte-derived VEGF mediates survival and tube stabilization of hypoxic brain microvascular endothelial cells in vitro. Brain Res Dev Brain Res. 2001 Sep 23; 130(1): 123-32.
[3] Papavassiliou E, Gogate N, Proescholdt M, et al. Vascular endothelial brain. J Neurosci Res, 1997, 49:451-460.
[4] 吴雪海,高亮,亚平等.闭合性颅脑损伤血浆血管内皮细胞生长因子的变化和意义[J]中国急诊医学杂志, 2003 Dec 12; 830-832
[5] Sun Y, Jin K, Xie L, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia[J]. J Clin Invest. 2003,111(12): 1843-51.
[6] Isner JM, Takayuki A .Therapeutic angiogenesis. Front-Biosci. 1998 May 5; 3: e49-69
[7] Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures [J]. Neuroscience, 1999, 90(4): 1529-41.
[8] Rovak JM, Mungara AK, Aydin MA, et al. Effects of vascular endothelial growth factor on nerve regeneration in a cellular nerve grafts [J]. Reconstr Microsurg, 2004, 20(1): 53-8.
[9] Christenson SD, Lake KD, Ooboshi H, et al. Adenovirus-mediated gene transfer in vivo cerebral blood vessels and perivascular tissue in mice [J]. Stroke, 1998, 29(7): 1411-1415.
[10] 饶宜光,褚晓凡,付学军等.不同途径导入 rAAV-VEGF165 基因对大鼠脑缺血边缘区血管生成的影响[J].中风与神经疾病杂志, 2006, 23(2):217-219.
[11] Kusaka N,Sugiu K,Tokunaga K,et al. Enhanced brain angiogenesis in chronic cerebral hypoperfusion after administration of plasmid human vascular endothelial growth factor in combination with indirect vasoreconstructive surgery[J]. J Neurosurg, 2005, 103(5): 882-90.
[1] 韩久卉,张英泽.中枢神经系统对腺病毒载体的免疫应答[J].中华微生物学和免疫学杂志,2006,26(9):863-866。
[2] Araki K, Shiotani A, Watabe K, et al. Adenoviral GDNF gene transfer enhances neurofunctional recovery after recurrent laryngeal nerve injury [J]. Gene Ther, 2006; 13(4): 296-303.
[3] Doi K, Nibu K, Ishida H, Okado H, et al. Adenovirus-mediated gene transfer in olfactory epithelium and olfactory bulb: a long-term study [J]. Ann Otol Rhinol Laryngol ,2005; 114(8): 629-633.
[4] Gauthier R, Joly S, Pernet V, et al. Partial correction of sensitivity to oxidant stress in Friedreich ataxia patient fibroblasts by frataxin-encoding adeno-associated virus and lentivirus vectors [J]. Hum Gene Ther, 2005; 16(8): 947-956
[5] 石忠松,黄正松,郭少雷等.重组腺病毒载体介导外源基因转移至痉挛脑血管的研究[J].中华实验外科杂志,2004,21(10):1239-1240.
[6] 吴伟.重组腺病毒载体转导的脑源性神经生长因子在大鼠体外培养海马神经元谷氨酸损伤模型中的保护作用[J].中华神经科杂志 2005,38(7 ):457-459
[1] Perri B R, Smith D H, Murai H, et al. Metabolic quantification of lesion volume following experimental traumatic brain injury in the rat[J]. J Neurotrauma,1997,114(1):15-22.
[2] Dixon CE, Lyeth BG, Povlishock JT,et al. A fluid percussion model of experimental brain injury in the rat[J]. J Neurosurg,1987,67(1):110-119.
[3] 李力仙,王天佑,钟震宇等.自由落体和液压致大鼠脑损伤的对比研究.中华实验外科杂志,1999,16(5):447-448。
[4] Sullivan HG, Martinez J, Becker DP, et al. Fluid-percussion model of mechanical brain injury in the cat[J]. J Neurosurg.1976;45:520-534.
[5] Feeney DM,Boyeson MG,Linn RT,et al. Methodology and local effects of contusion in the rat[J].Brain Res.1981;211(1):67-77
[6] 王国强,廖维宏,李芳等.创伤性脑损伤诱导海马细胞凋亡模型的建立[J].第三军医大学学报,2000,Vol.22 No.9,P.826-830.
[7] Yano A, Shingo T, Takeuchi A,et al. Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia[J]. J Neurosurg. 2005, 103(1): 104-14.
[8] Rosenstein JM, Mani N, Sliverman WF, et al. Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and vivo[J]. Proc Natl Acad Sci USA, 1998, 95(12): 7086-91.
[9] 孟云,陈吉相,孙圣刚.脑室注射 VEGF-165 对实验性脑出血大鼠血脑屏障的影响[J].卒中与神经疾病,2006,13(2):79-81.
[10] Christenson SD, Lake KD, Ooboshi H, et al. Adenovirus-mediated gene transfer in vivo cerebral blood vessels and perivascular tissue in mice [J]. Stroke, 1998, 29(7):1411-1415.
[11] 饶宜光,褚晓凡,付学军等.不同途径导入 rAAV-VEGF165 基因对大鼠脑缺血边缘区血管生成的影响[J].中风与神经疾病杂志,2006,23(2):217-219.
[12] 徐忠铧,唐文渊,朱晓峰.转基因干细胞移植对脑外伤大鼠的保护作用[J].中国急救医学,2006,(26)7,515-517.
[1] 蒲传强,郎森阳,吴卫平,编著.脑血管病学.北京:人民军医出版社,1999:141-145
[2] 邓平,徐小虎,陈耀文等.激光扫描共聚焦显微镜观察脑干中的神经轴突[J].中华物理学杂志,2000,22(1):23-24.
[3] Smith FM, Horsburgh K, Nicoll JAR, et al. TUNEL staining of contusions after fatal head injury in man [J]. Neurotrauma, 1998, 15:54-59.
[4] Ng I, Yeo TT, Tang WY, et al. Apoptosis occurs after cerebral contusion in humans [J]. Neurosurgery, 2000,46(4): 949-956.
[5] 王国强,廖维宏,李芳等.创伤性脑损伤诱导海马细胞凋亡模型的建立[J].第三军医大学学报,2000,(22)9:826-830.
[6] Montal M. Mitochondria, glutamate neurotoxicity and the death cascade[J]. Biochim Biophys Acta,1998,1 366(1-2):113-126.
[7] Kitamura Y, Ota T, Matsuoka Y, et al. Hydrogen peroxide-induced apoptosis mediated by p53 protein in glial cells[J]. Glia, 1999, 25(2): 154-164.
[8] Levick Y, Coffey HD, Mello SR. opposing effects of thapsigargin at survival of developing cerebrallar granule neurons in culture [J]. Brain Res, 1995,676(2): 325-335.
[9] Pizzi M, Coffi F, Boroni F, et al. opposing roles for NF-KB reflector P65 and c-Rel in the modulation of neuron survival elicited by glutamate and interleukin-1 beta [J].Biol Cherm,2002,277(28):20717-20723.
[10] Iwasaki Y, Ikeda K. Prevention by insulin-like growth factor-1 and rilozole in motor neuron death after neonatal axotomay[J].Neurol Sci,1999,169:148-155.
[11] 周乐,师蔚,孙建军等.亚低温对脑外伤后细胞调亡影响[J].西安交通大学学报(医学版),2003,24(4):342-344.
[12] Jin KL, Mao XO, Greenberg DA, et al. Vascular endothelial growth factor: director neuroprotective effect in vitro ischemia [J]. PNAS, 2000,97(18): 10 242-10 247
[13] 陈兴洲,陆立勋.血管内皮细胞生长因子与脑缺血[J].国外医学:脑血管疾病分册, 1997,(5):259-262.
[14] Alon T, Hemo I, Itin A, et al. Vascular endothelial growth factor acts as a survival factor for newlyformed retinal vessels and has implication for fretinopathy ofprematrurity[J]. Nat Med, 1995,1:1 024-1 028
[15] Jin KL, Mao XO, Greenberg DA. Vascular endothelial growth factor: direct neuroprotective effect in vitro ischemia [J]. Proc Natl Acad Sci U S A.2000, 29,97(18): 10242-7.
[16] Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures [J]. Neuroscience, 1999, 90(4): 1529-41.
[17] Zhang QK, Magovern CJ, Mack CA, et al. Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediated angiogenesis [J]. J Surg Res, 1997, 67(3): 147-154.
[18] Sk?ld MK, Risling M, Holmin S. Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration [J].Eur J Neurosci,2006, 23(1): 21-34.
[1] Wintermark M, Chiolero R, Van Melle G, et al. Cerebral vascular autoregulation assessed by perfusion-CT in severe head trauma patients[J]. J Neuroradiol, 2006, 33(1):27-37.
[2] Dohmen C, Bosche B, Graf R, et al. Identification and clinical impact of impaired cerebrovascular autoregulation in patients with malignant middle cerebral artery infarction[J]. Stroke, 2007, 38(1):56-61.
[3] Wintermark M, van Melle G, Schnyder P, et al. Admission perfusion CT: prognostic value in patients with severe head trauma [J]. Radiology, 2004, 232(1):211-20.
[4] Wintermark M, Chioléro R, van Melle G, et al. Relationship between brain perfusion computed tomography variables and cerebral perfusion pressure in severe head trauma patients[J]. Crit Care Med, 2004, 32(7):1579-87.
[5] Wintermark M, Cotting J, Roulet E, et al. Acute brain perfusion disorders in children assessed by quantitative perfusion computed tomography in the emergency setting[J]. Pediatr Emerg Care, 2005, 21(3):149-60.
[6] 王 忠 诚 , 主 编 . 王 忠 诚 神 经 外 科 学 . 第 一 版 , 湖 北 , 湖 北 科 学 技 术 出 版社,2005:370-371.
[7] K.A. Miles. Brain perfusion: computed tomography applications [J].Neuroradiology, 2004, 46(s): 194–200.
[8] Harada JN, Lee LY, Patel SR, et al. Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor[J].Ann Thorac Surg,2000.69(1):14
[9] 蒋国顺,朱朗标,高长青等.VEGF165cDNA 治疗缺血性心肌后心肌灌注和代谢的变化[J].解放军医学杂志,2002,27(3):217-218.
[10] 武柏林,刘怀军,汪国石等.MR 灌注成像对 VEGF 质粒治疗犬脑梗塞效果评价的实验研究[J].中国临床医学影像杂志,2003,14(5):310-315.
[11] Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures[J]. Neuroscience, 1999, 90(4): 1529-41.
[12] Rosenstein JM, Mani N, Sliverman WF, et al. Patterns of brain angiogenesis aftervascular endothelial growth factor administration in vitro and vivo[J]. Proc Natl Acad Sci USA, 1998, 95(12):7086-91.
[13] Christenson SD, Lake KD, Ooboshi H, et al. Adenovirus-mediated gene transfer in vivo cerebral blood vessels and perivascular tissue in mice [J]. Stroke, 1998, 29(7):1411-1415.
[14] 饶宜光,褚晓凡,付学军等.不同途径导入 rAAV-VEGF165 基因对大鼠脑缺血边缘区血管生成的影响[J].中风与神经疾病杂志,2006,23(2):217-219.
[1] Infanger M, Schmidt O, Kossmehl P, et al. Vascular endothelial growth factor serum level is strongly enhanced after burn injury and correlated with local and general tissue edema [J].Burn, 2004,30(4):305-311.
[2] Corral CJ, Siddiqui A, Wu L, et al. Vascular endothelial growth factor is important than basic fibroblastic growth factor during ischemic wound healing [J]. Arch surg, 1999, 134(2):200-205.
[3] Pilch H, Schlenger K, Steiner E, et al. Hypoxia-stimulated expression of angiogenic growth factors in cervical cancer cell and cervical cancer-drivered fibroblasts[J]. Int J Gynecal Cancer, 2001, 11(2):137-142.
[4] 史福平,王珊,张国华.血管内皮细胞生长因子在脑血管病中的研究进展.综述[J]. 临床神经病学杂志,2006,19(3).234-236.
[5] Zhang QK, Magovern CJ, Mack CA, et al. Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediatedangiogenesis[J]. J Surg Res, 1997, 67(3):147-154.
[6] Rovak JM, Mungara AK, Aydin MA, et al. Effects of vascular endothelial growth factor on nerve regeneration in a cellular nerve grafts[J]. J Reconstr Microsurg, 2004, 20(1): 53-8.
[7] Facchiano F, Fernandez E, Mancarella S, et al. Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor[J]. J Neurosurg, 2002, 97(1): 161-8.
[8] Jin K,Zhu Y,Sun Y, et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo[J]. Proc-Natl-Acad-Sci-U-S-A, 2002, 99(18): 11946-50.
[9] Jin K, Mao XO, Greenberg DA,et al. Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling[J]. J Neurobiol, 2006, 66(3):236-42.
[10] Kovacs Z, Ikezaki K, Samoto K, et al. VEGF and flt. Expression time kinetics in rat brain infarct[J]. Stroke, 1996, 27(10): 1865-72.
[11] Issa R, Krupinski J, Bujny T, et al. Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke[J]. Lab-Invest, 1999, 79(4): 417-25.
[12] 张爱梅,李宪章,靳光娴等.缺血性血管病患者血清 VEGF 和 IL-1β的变化及意义[J].临床神经病学杂志,2002,15(6):341-343.
[13] NIssen NN, Polverini PJ, Koch AE, et al, Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing[J]. Am J Pathol, 1998, 152(6):1445-1452.
[14] Chow J, Ogunshola O Fan SY ea al, Astrocyte-derived VEGF mediates survival and tube stabilization of hypoxic brain microvascular endothelial cells in vitro[J]. Brain Res Dev Brain Res, 2001, 130(1): 123-32.
[15] Papavassiliou E, Gogate N, Proescholdt M, et al. Vascular endothelial growth factor(vascular permeability factor) expression in injuried rat brain[J]. J Neurosci Res, 1997, 49:451-460.
[16] 吴雪海,高亮,金亚平等.闭合性颅脑损伤血浆血管内皮细胞生长因子的变化和意义[J].中国急诊医学杂志,2003 Dec 12: 830-832.
[17] 吴克荣,催建华,顾玉林等.大鼠冲击损伤后 VEGF 的表达与损伤后存活时间关系的实验研究[J].南通大学学报,2006,26(2):85-87.
[18] 吕文,陈建良,杨地等.bFGF、VEGF 在大鼠创伤脑组织中的表达及关系[J].中风与神经疾病杂志, 2004,21(1):33-35.
[19] Sk?ld MK, von Gertten C, Sandberg-Nordqvist AC, et al. VEGF and VEGF receptor expression after experimental brain contusion in rat[J]. J Neurotrauma, 2005, 2(3):353-67.
[20] Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures[J]. Neuroscience, 1999, 90(4): 1529-41.
[21] Rovak JM, Mungara AK, Aydin MA,et al. Effects of vascular endothelial growth factor on nerve regeneration in acellular nerve grafts[J]. J Reconstr Microsurg, 2004, 20(1): 53-8.
[22] Hayashi T, Abe K, Itoyama Y. Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia[J]. J Cereb Blood Flow Metab, 1998, 18(8): 887-95.
[23] Zhang ZG, Zhang L, Tsang W, et al. Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after foca cerebral ischemia[J]. J Cerebral Blood Flow Metab, 2002, 22(4):379-392.
[24] Nag S, Eskandarian MR, Davis J, et al. Differential expression of vascular endothelial growth factor-A (VEGF-A) and VEGF-B after brain injury[J]. J Neuropathol Exp Neurol, 2002, 61(9): 778-88.
[25] Yano A, Shingo T, Takeuchi A, et al. Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia[J]. J Neurosurg, 2005 , 103(1): 104-14.
[26] Rosenstein JM, Mani N, Sliverman WF, et al. Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and vivo[J]. Proc Natl Acad Sci USA, 1998, 95(12):7086-91.
[27] 孟云,陈吉相,孙圣刚.脑室注射 VEGF-165 对实验性脑出血大鼠血脑屏障的影响[J].卒中与神经疾病,2006,13(2):79-81.
[28] Christenson SD, Lake KD, Ooboshi H, et al. Adenovirus-mediated gene transfer in vivo cerebral blood vessels and perivascular tissue in mice [J]. Stroke, 1998,29(7):1411-1415.
[29] 饶宜光,褚晓凡,付学军等.不同途径导入 rAAV-VEGF165 基因对大鼠脑缺血边缘区血管生成的影响[J].中风与神经疾病杂志,2006, 23(2):217-219.
[30] Kusaka N,Sugiu K,Tokunaga K,et al. Enhanced brain angiogenesis in chronic cerebral hypoperfusion after administration of plasmid human vascular endothelial growth factor in combination with indirect vasoreconstructive surgery[J]. J Neurosurg, 2005, 103(5): 882-90.
[31] van Bruggen N, Thibodeaux H, Palmer JT, et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain[J]. J Clin Invest, 1999, 104(11):1613-20.
[32] Sk?ld MK, Risling M, Holmin S. Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration[J]. Eur J Neurosci, 2006, 23(1):21-34.
[1] Miles KA, Hayball MP, Dixon AK. Color perfusion imaging: a new application of computed tomography[J]. Lancet, 1991, 337(3): 643-645.
[2] Miles KA. Measurement of tissue perfusion by dynamic computed tomography [J]. Br J Radiol,1991,64(761): 409-412.
[3] K.A. Miles. Brain perfusion: computed tomography applications [J]. Neuroradiology, 2004,46(s): 194–200.
[4] Nabavi DG, Cenic A, Craen RA, et al. CT assessment of cerebral perfusion: experimental validation and initial clinical experience[J]. Radiology,1999,213(1): 141-149.
[5] Eastwood JD, Lev MH, Azhari T, et al. CT perfusion scanning with deconvolution analysis: pilot study in patients with acute middle cerebral artery stroke [J]. Radiology, 2002, 222(1): 227-236.
[6] Lawrence KS, Lee TY .An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: II. Experimental validation [J].J-Cereb-Blood-Flow-Metab, 1998 ,18(12): 1378-85.
[7] Lawrence KS, Lee TY. An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: I. Theoretical derivation[J].J-Cereb-Blood-Flow-Metab, 1998 ,18(12): 1365-77.
[8] 刘翔,戴建平,孙波等.CT 灌注成像在脑内缺血性疾病中的初步应用[J].中华放射学杂志,1999,33: 452-455.
[9] Koenig M, Klotz E, Luda B, et al. Perfusion CT of the brain: diagnostic approach for early detection of ischemic stroke [J]. Radiology, 1998, 209:85-93.
[10] 张红梅,高培毅,胡平英.脑组织血流灌注的动态 CT 定量研究[J].中华放射学杂志,1999,33:448-451.
[11] Koenig M, Dphil EK, Luda B, et al. Perfusion CT of the brain: new diagnostic approach for early detection of ischemic stroke [J]. Radiology, 1996, 201:236.
[12] Gillard JH, Bearcroft PW, Miles KA. et, al. Evaluation of quantitative cerebral CT perfusion with positron emission tomography: preliminary results [J]. Radiology, 1997, 205:185.
[13] Klotz E, Koeng M. Perfusion measurements of the brain: using dynamic CT for the qantitative assessment of cerebral ischemia in acute stroke [J]. Eur J Radiol, 1999, 30:170-184.
[14] Kloska SP, Fischer T, Nabavi DG, et, al. Comparison of Different Iodine Concentration Contrast Media in Perfusion Computed Tomography of the Brain: Is High Iodine Concentration Useful? [J]. Invest Radiol, 2007 ,42(8):564-8.
[15] Wintermark M., Lepori D, Cotting J, et al. Brain Perfusion in Children: Evolution With Age Assessed by Quantitative Perfusion Computed Tomography [J]. Pediatrics,2004 ,113 (6) :1642-52.
[16] Reichenbach JR, Rother J, Jonetz-Mentzel, et al. Acute stroke evaluated by time-to-peak mapping during initial and early follow-up perfusion CT studies [J]. AJNR, 1999, 20:1842-1850.
[17] Gobbel CT, Cann CE, Fike JR. Comparison of xenon-enhanced CT with ultrafast CT for measurement regional cerebral blood flow [J]. AJNR, 1993, 14:543-550.
[18] Wirestam R, Ryding E, Lindgren A, et al. Regional cerebral blood flow distributions in normal volrnteers: dynamic susceptibility contrast MRI compared with 99m Tc-HMPAO-SPECT [J]. J Comput Assist Tomogr, 2000, 24:526-530.
[19] Hunter GJ, Hamberg LM, Ponzo JA, et al. Assessment of cerebral perfusion and arterial anatomy in hyperacute stroke with three-dimensional functional CT: early clinical results [J]. AJNR, 1998, 19:29-37.
[20] Hamberg LM, Hunter GJ, Kierstead D, et al. Measruement of quantitative CBV with subtraction three-dimensional functional CT [J]. AJNR, 1996, 17:1961-1869.
[21] Shih TTF, Huang KM. Acute stroke: detection of changes in cerebral Perfusion with dynamic CT scanning [J]. Radiology, 1988, 169:469-174.
[22] Scharf J, Brockmann MA, Daffertshofer M, et al. Improvement of Sensitivity and Interrater Reliability to Detect Acute Stroke by Dynamic Perfusion Computed Tomography and Computed Tomography Angiography[J] .J Comput Assist Tomogr, 2006 ,30(1):105-10.
[23] 周丽红,王嗣欣,赵亮等.症状性颅内外动脉狭窄内支架成型术前后脑灌注 CT 成像的变化及与临床疗效的关系[J].中国神经精神疾病杂志,2007,(33)1,51-53
[24] Wintermark M. Relationship between brain perfusion computed tomography variables and cerebral perfusion pressure in severe head trauma patients[J]. Crit Care Med,2004,32(7):1621-3.
[25] Wintermark M, van Melle G, Schnyder P. et, al. Admission perfusion CT: prognostic value in patients with severe head trauma[J]. Radiology, 2004, 232(1): 211-220.
[26] Wintermark M, Chiolero R, Van Melle G, et al. Cerebral vascular autoregulation assessed by perfusion-CT in severe head trauma patients[J]. J Neuroradiol, 2006, 33(1): 27-37
[27] Wintermark M, van Melle G, Schnyder P, et al. Prognostic value of admission perfusion-CT in severe head trauma patients[J]. Radiology, 2004, 232:211-220.
[28] Qureshi AI, Kirmani JF, Xavier AR, et al. Computed tomographic angiography for diagnosis of brain death[J]. Neurology, 2004, 62(4):652-3.
[29] Hemphill JC, Smith WS, Sonne DC, et al. Relationship between brain tissue oxygen tension and CT perfusion: feasibility and initial results [ J ] . AJNR-Am-J-Neuroradiol, 2005, 26(5): 1095-100.
[30] Charles B. L. M. Majoie, Leonard J. van Boven, Diederik van de Beek, et, al. Perfusion CT to Evaluate the Effect of Transluminal Angioplasty on CerebralPerfusion in the Treatment of Vasospasm After Subarachnoid Hemorrhage[J]. Neurocrit Care, 2007, 06:40–44.
[31] 于涛,王中,周岱等.应用CT灌注成像研究兔蛛网膜下腔出血后脑血流的变化[J].江苏医药,2005(31)9,683-685.
[32] Sviri, Gill E. Dynamic Perfusion Computed Tomography in the Diagnosis of Cerebral Vasospasm[J]. Neurosurgery, 2006, 59(2): 319-325
[33] Turowski B, Haenggi D, Wittsack J, et al. Cerebral perfusion computerized tomography in vasospasm after subarachnoid hemorrhage: diagnostic value of MTT[J]. Rofo, 2007, 179(8): 847-54.
[34] Pham M, Johnson A., Bartsch AJ, et, al. CT perfusion predicts secondary cerebral infarction after aneurysmal subarachnoid hemorrhage[J ].Neurology, 2007, 69:762-765
[35] 丁陪,凌华威,张欢等.胶质瘤 CT 灌注成像对脑血容量与血管表面通透性的相关研究[J].中华放射学杂志 2007,(41)1: 25-28
[36] Lev MH, Ozsunar Y, Henson JW, et al. Glial tumor grading and outcome prediction using dynamic spin-echo MR susceptibility mapping compared with conventional contrast-enhanced MR: confounding effect of elevated rCBV of oligodendrogliomas[J]. AJNR, 2004, 25:214-221.
[37] Yeung WT, Lee TY, Del Maestro RF, et al. Effect of steroids on iopamidol blood-brain transfer constant and plasma volume in brain tumors measured with X-ray computed tomography[J]. J Neurooncol, 1994, 18:53–60.
[38] Bondestam S, Halavaara J T., Jaaskelainen J E. Perfusion CT of the Brain in the Assessment of Flow Alterations during Brachytherapy of Meningioma[J]. Acta Radiologica, 1999, 40(5): 469-473.
[39] Leggett DA, Miles KA, Kelley BB. Blood-brain barrier and blood volume imaging of cerebral glioma using functional CT: a pictorial review[J].Australas Radiol, 1998, 42:335-340.