针刺足三里对脑出血大鼠脑内缺氧诱导因子-1α和血管内皮生长因子表达的影响
|
摘要
目的脑出血(intracerebral hemorrhage, ICH)是一种常见的中风亚型,以其高发病率,严重的致死率和致残率而受到人们越来越多的关注。但是目前除了外科手术清除血肿和脱水降颅内压外,尚无其它有效的治疗方法。足三里为足阳明胃经合穴,目前关于针刺足三里在脑出血中的实验和临床研究主要集中于抑制神经细胞凋亡,促进神经功能恢复等方面。本研究通过观察针刺足三里对脑出血后缺氧诱导因子-1α(hypoxia-inducible factor-1α, HIF-1α)和血管内皮生长因子(vascular endothelial growth factor, VEGF)表达的影响,初步探讨针刺足三里治疗脑出血的作用机制。
方法120只SD大鼠随机分为假手术组(30只)、假针刺组(30只)、脑出血组(30只)、针刺组(30只),通过立体定位向脑内苍白球注入Ⅶ型胶原酶0.5U建立脑出血模型。假手术组注入等体积生理盐水。针刺组针刺双侧足三里,假针刺组针刺大鼠双侧非经非穴处皮肤。采用免疫组化方法观察各组3、7、14天HIF-1α和VEGF表达的空间位置变化和蛋白表达情况；运用实时荧光定量PCR (Real-time polymerase chain reaction, RT-PCR)检测各组造模术后3、7、14天各时间点HIF-1α和VEGF mRNA表达的动态变化。
结果假手术组不同时间点HIF-1a和VEGF未见明显表达。脑出血组、假针刺组和针刺组3天时在血肿周围均可观察到大量HIF-1α和VEGF阳性微血管,7天HIF-1α和VEGF阳性微血管开始深入血肿区,随后出现在血肿区。脑出血3天时HIF-1α蛋白表达即显著增高,随后逐渐降低。VEGF蛋白表达从3天时即明显升高,一直持续到14天。针刺组HIF-1α蛋白、VEGF蛋白表达水平较脑出血组显著升高(P<0.01),而假针刺组与脑出血组比较无统计学意义。
RT-PCR结果显示：假手术组、假针刺组、脑出血组和针刺组HIF-1αmRNA表达水平无明显差异；VEGF mRNA在假手术组未见明显表达,脑出血后3天VEGF mRNA表达即明显增强,一直持续到14天,针刺组VEGF mRNA表达水平在各时间点均明显高于脑出血组(P<0.05),而假针刺组与脑出血组比较差异无统计学意义。
结论针刺足三里能促进脑出血大鼠脑内HIF-1α和VEGF表达,可能有利于脑出血损伤区的微血管系统重建,从而实现损伤组织的修复。
Objective Intracerebral hemorrhage(ICH) is a common and often fatal stroke subtype, to which an increasing number of people are paying close attention because of its high morbility, mortality and mutilation rate. However, currently there is no medical therapy available for those patients except blood pressure reduction and neurosurgical evacuation of the hematoma. The Zusanli (ST36) is the He-sea acupoint of Stomach Meridian of Foot-Yangming(ST). Clinical and experimental studies on ICH by acupunctrue at the Zusanli are focused on aspects of inhibiting the apoptosis of neurons and promoting neurological functional recovery. To investigate the mechanisms of acupunctrue at the Zusanli (ST36), the expressions of hypoxia-inducible factor-la (HIF-1α) and vascular endothelial growth factor (VEGF) were observed in damaged region of rats'brains after intracerebral hemorrhage (ICH).
Methods The ICH models were established by injecting collagenase typeⅦ0.5U stereotaxically into right globus pallidus in rats. Animals were randomly divided into four groups:sham-operation (SO), ICH+NA (EA therapy on non-acupoint), ICH and ICH+EA group (EA therapy on Zusanli). The same volume of saline was given to the SO group. The spatial distribution and protein expression of HIF-la and VEGF in each group were observed by immunohistochemistry on day3、7and14 after modeling. In the meantime, the dynamic changes of VEGF and HIF-la mRNA expressions in all groups were assayed by Real-time polymerase chain reaction (RT-PCR).
Results No significant expression of HIF-la and VEGF in the Sham-operative group was found during the experiment. In ICH, ICH+NA and ICH+EA groups, many VEGF immunoreactive microvessels of the dilated outline were detected in the perihematomal tissue from 3 days, and the vessels extended into the clot from the surrounding area at about 7 days, then appeared in the clot thereafter. HIF-la protein level significantly increased from 3 days, then began to decline. The expression of VEGF protein in ICH group increased gradually from day 3 to day 14. But ICH+EA group of HIF-la and VEGF protein expression were significantly higher than that in ICH group at the corresponding time points(P<0.01). There was no statistic significance between ICH+NA and ICH groups.
HIF-1αmRNA levels were unchanged in SO, ICH+NA, ICH and ICH+EA group. There was no obvious expression of VEGF mRNA in rat brains of sham-operates groups. The VEGF mRNA expression in ICH group increased gradually from day 3 to day 14, ICH+EA group was significantly higher than ICH group at the corresponding time points(P<0.05). There was no statistic significance between ICH+NA and ICH groups.
Conclusions The acupuncture zusanli therapy promote VEGF expression in brain of intracerebral hemorrhagic rats, which may accelerate the angiogenesis in the reconstruction of microvascular network in the damaged zone, and facilitate the repair of damaged tissue.
方法120只SD大鼠随机分为假手术组(30只)、假针刺组(30只)、脑出血组(30只)、针刺组(30只),通过立体定位向脑内苍白球注入Ⅶ型胶原酶0.5U建立脑出血模型。假手术组注入等体积生理盐水。针刺组针刺双侧足三里,假针刺组针刺大鼠双侧非经非穴处皮肤。采用免疫组化方法观察各组3、7、14天HIF-1α和VEGF表达的空间位置变化和蛋白表达情况；运用实时荧光定量PCR (Real-time polymerase chain reaction, RT-PCR)检测各组造模术后3、7、14天各时间点HIF-1α和VEGF mRNA表达的动态变化。
结果假手术组不同时间点HIF-1a和VEGF未见明显表达。脑出血组、假针刺组和针刺组3天时在血肿周围均可观察到大量HIF-1α和VEGF阳性微血管,7天HIF-1α和VEGF阳性微血管开始深入血肿区,随后出现在血肿区。脑出血3天时HIF-1α蛋白表达即显著增高,随后逐渐降低。VEGF蛋白表达从3天时即明显升高,一直持续到14天。针刺组HIF-1α蛋白、VEGF蛋白表达水平较脑出血组显著升高(P<0.01),而假针刺组与脑出血组比较无统计学意义。
RT-PCR结果显示：假手术组、假针刺组、脑出血组和针刺组HIF-1αmRNA表达水平无明显差异；VEGF mRNA在假手术组未见明显表达,脑出血后3天VEGF mRNA表达即明显增强,一直持续到14天,针刺组VEGF mRNA表达水平在各时间点均明显高于脑出血组(P<0.05),而假针刺组与脑出血组比较差异无统计学意义。
结论针刺足三里能促进脑出血大鼠脑内HIF-1α和VEGF表达,可能有利于脑出血损伤区的微血管系统重建,从而实现损伤组织的修复。
Objective Intracerebral hemorrhage(ICH) is a common and often fatal stroke subtype, to which an increasing number of people are paying close attention because of its high morbility, mortality and mutilation rate. However, currently there is no medical therapy available for those patients except blood pressure reduction and neurosurgical evacuation of the hematoma. The Zusanli (ST36) is the He-sea acupoint of Stomach Meridian of Foot-Yangming(ST). Clinical and experimental studies on ICH by acupunctrue at the Zusanli are focused on aspects of inhibiting the apoptosis of neurons and promoting neurological functional recovery. To investigate the mechanisms of acupunctrue at the Zusanli (ST36), the expressions of hypoxia-inducible factor-la (HIF-1α) and vascular endothelial growth factor (VEGF) were observed in damaged region of rats'brains after intracerebral hemorrhage (ICH).
Methods The ICH models were established by injecting collagenase typeⅦ0.5U stereotaxically into right globus pallidus in rats. Animals were randomly divided into four groups:sham-operation (SO), ICH+NA (EA therapy on non-acupoint), ICH and ICH+EA group (EA therapy on Zusanli). The same volume of saline was given to the SO group. The spatial distribution and protein expression of HIF-la and VEGF in each group were observed by immunohistochemistry on day3、7and14 after modeling. In the meantime, the dynamic changes of VEGF and HIF-la mRNA expressions in all groups were assayed by Real-time polymerase chain reaction (RT-PCR).
Results No significant expression of HIF-la and VEGF in the Sham-operative group was found during the experiment. In ICH, ICH+NA and ICH+EA groups, many VEGF immunoreactive microvessels of the dilated outline were detected in the perihematomal tissue from 3 days, and the vessels extended into the clot from the surrounding area at about 7 days, then appeared in the clot thereafter. HIF-la protein level significantly increased from 3 days, then began to decline. The expression of VEGF protein in ICH group increased gradually from day 3 to day 14. But ICH+EA group of HIF-la and VEGF protein expression were significantly higher than that in ICH group at the corresponding time points(P<0.01). There was no statistic significance between ICH+NA and ICH groups.
HIF-1αmRNA levels were unchanged in SO, ICH+NA, ICH and ICH+EA group. There was no obvious expression of VEGF mRNA in rat brains of sham-operates groups. The VEGF mRNA expression in ICH group increased gradually from day 3 to day 14, ICH+EA group was significantly higher than ICH group at the corresponding time points(P<0.05). There was no statistic significance between ICH+NA and ICH groups.
Conclusions The acupuncture zusanli therapy promote VEGF expression in brain of intracerebral hemorrhagic rats, which may accelerate the angiogenesis in the reconstruction of microvascular network in the damaged zone, and facilitate the repair of damaged tissue.
引文
[1]徐新献.周崇伦.内科常见病症现代治疗.成都：四川科学技术出版社,2006：666.
[2]张玉琴,刘诗翔.脑出血的流行病学研究进展.神经损伤与功能重建,2007,2(3)：174-176.
[3]饶明俐.中国脑血管病防治指南.北京：人民卫生出版社,2005：56.
[4]Morgan T,Zuccarello M,Narayan R,et al.Preliminary findings of the minimatly-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial.Aeta Neurochir Suppl,2008,105:147.
[5]Bereczki D,Mihalka L,Szatmari S,et al.Mannitol use in acute stroke:case fatality at 30 days and 1 year.Stroke,2003,34:1730-1735.
[6]吴子辉,吴林.毒为出血性中风至笃之本——三因级联内毒为本.广西中医药,2005,28(1)：49-50.
[7]李富汗.略论血瘀与中风.国医论坛,2003,18(1)：43-44.
[8]Ward NL,Dumont DJ.The angiopoietins and Tie2/Tek:adding to the complexity of cardiovascular development.Semin Cell Dev Biol,2002,13(1):19-27.
[9]Folkman J.Angiogenesis in cancer,vascular,rheumatoid and other disease.Nat Med,1995,1(1):27-31.
[10]Jain RK,Schlenger K,Hockel M,et al.Quantitative angiogenesis assays:progress and problems.Nat Med,1997,3(11):1203-1208.
[11]Gimbrone MA,Leapman SB,Cotran RS,et al.Tumor angiogenesis:iris neovascularization at a distance from experimental intraocular tumors.Natl Cancer Inst.1973,50(1):219-228.
[12]Rafii S,Lyden D,Benezra R,et al.Vascular and haematopoietic stem cells:novel targets for anti-angiogenesis therapy?Nature Rev Cancer.2002,2(11)826-835.
[13]Nobutada M,Ozan Ak,Anthony GD,et al.Electro-Acupuncture at the Zusanli,Yanglingquan,and Kunlun Points Does Not Reduce Anesthetic Requirement.Anesth Analq,2002,95(1):98-102.
[14]Liu XY,Zhou HF,Pan YL,et al.Electro-acupuncture stimulation protects dopaminergic neurons from inflammation-mediated damage in medial forebrain bundle-transected rats.Exp Neurol,2004,189(1):189-196.
[15]Cho NH,Lee JD,Cheong BS,et al.Acupuncture suppresses intrastriatal hemorrhage-induced apoptotic neuronal cell death in rats.Neuroscience Letters,2004,362(2):141-145.
[16]张化彪,黎杏群,张铭湘.脑溢安对脑出血大鼠脑内碱性成纤维生长因子mRNA和肿瘤坏死因子蛋白表达的影响.中国中西医结合杂志,2002,22(7)：518-521.
[17]Tang T,Liu XJ,Zhang ZQ,et al.Cerebral angiogenesis after collagenase-induced intracerebral hemorrhage in rats.Brain Res,2007,1175:134-142.
[18]Rosenberg GA,Mun-Bryce S,Wesley M,et al.Collagenase-induced intracerebral hemorrhage in rats.Stroke,1990,21 (5):801-807.
[19]远山正弥.神经科学尖端技术手册-分子组织化学.北京科学出版社,第一版,1998.
[20]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.Methods,2001,25(4):402-408.
[21]Zhang ZQ,Tang T.Effect of Qi-tonifying and Stasis-eliminating Therapy(益气活血法)on Expression of Vascular Endothelial Growth Factor and Its Receptors Flt-1,Flk-1 in the Brain of Intracerebral Hemorrhagic Rats.Chin J Integr Med,2007,13(4):285-290.
[22]Freeburg PB, Abrahamson DR.Hypoxia-inducible factors and kidney vascular development.Am Soc Nephrol,2003,14:2723-2730.
[23]Zhang ZQZhang L,Tsang W,et al.Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischernia.Cerebral Blood Flow Metab,2002,22(4):379-392.
[24]张化彪,黎杏群,张铭湘.脑溢安对脑出血大鼠脑内碱性成纤维生长因子mRNA和肿瘤坏死因子蛋白表达的影响.中国中西医结合杂志,2002；22(7)：518-521.
[25]Seagroves TN,Peacock DL,Liao D,et al.VHL Deletion Impairs Mammary Alveologenesis But Is Not Sufficient for Mammary Tumorigenesis.Am J Pathol,2010; 175(5):2269-82.
[26]张苏明,唐洲平.脑出血临床研究评价.中华神经科杂志,2003,36：241-242.
[27]刘庆新,苏长海,张苏明.脑出血血肿周围半暗带的病理生理研究进展.国外医学脑血管疾病分册,2002,6：425-427.
[28]Halterman MW,Federoff HJ.HIF-1α and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia.Exp Neurol,1999,159:65-72.
[29]Zhong H,De Marzo AM,Laughner E,et al.Overexpression of hypoxia-inducible factor-alpha in common human cancers and their metastases.Cancer Res,1999,59:5830-5835.
[30]Yu AY,Frid MG,Shimoda LA,et al.Temporal,spatial,and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol,1998,275:L818-L826.
[31]Jiang Y,Wu J,Keep RF,et al.Hypoxia-Inducible Factor-la Accumulation in the Brain After Experimental Intracerebral Hemorrhage.Cerebral Blood Flow Metab,2002;22(6):689-696.
[32]Marti HJ,Bernaudin M,Bellail A,et al.Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischernia.Am J Pathol,2000,156(3):965-976.
[33]Byzova TV,Goldman CK,Jankau J,et al.Adenvirus encoding vascular endothelial growth factor-D induces tissue specific vascular patterns in vivo.Blood,2002,99(12):4434-4442.
[34]刘庆新,张合亮,张苏明.高血压脑出血血肿周围脑组织缺氧诱导因子-1α的表达及意义.中华神经科杂志,2006,39(1)：24-26.
[35]尤艳利,周爽.缺氧诱导因子-1与脑出血的研究进展.中风与神经疾病杂志,2008,25(2)：245-247.
[36]Barnes PM,Powell-Griner E,McFann K,et al.Complementary and alternative medicine use among adults:United States,2002.Advance Data,2004,27(343):1-19.
[37]Haake M,Muller HH,Schade-Brittinger C,et al.German Acupuncture Trials for chronic low back pain:randomized,multicenter,blinded,parallel-group trial with 3 groups.Arch Intern Med,2007,167(17):1892-1898.
[38]Lu PK, Lu GP,Lu DP,et al.Managing acute withdrawal syndrome on patients with heroin and morphine addiction by acupuncture therapy.Acupunct.Electrother. Res,2004,29:187-195.
[39]Ou YW,Han L,Da CD,et al.Influence of acupuncture upon expressing levels of be fibroblast growth factor in rat brain flllowing focal cerebral ischemia-evaluated by time-resolved fluorescence immunoassay.Neurol Res,2001,23(1):47.
[40]Zhang SH,Liu M,Asplund K,et al.Acupuncture for Acute Stroke.Cochrane Database Syst Rev.2005,18(2):1337.34
[41]陈文,顾红卫,马维平,等.针刺足三里、悬钟对缺血性中风患者脑血管功能的影响：多中心随机对照研究.中国针灸,2006,26(12)：851-853.
[42]戚贵明.电针对脑缺血大鼠血清血管内皮生长因子及肿瘤坏死因子的影响：[硕士学位论文].湖北：湖北中医学院,2007.
[43]黑龙江省祖国医药研究所.针灸大成校释.北京：人民卫生出版社,1984,768-770.
[44]韩肖华,黄晓琳,李春芳,等.电针对脑缺血大鼠VEGF及Flk-1表达和细胞外钙离子浓度的影响.中国康复,2003,18(6)：329-331.
[45]Morioka N,Akca O,Doufas AG,et al.Electro-Acupuncture at the Zusanli,Yanglingquan,and Kunlun points does not reduce anesthetic requirement.Anesth Analq,2002;95(1):98-102.
[46]Cai SX,Yu WJ,Zhang L,et al.Effect of electroacupuncture on plasma endogenous endothelial progenitor cell counts in cerebral ischemia-reperfusion rats.Zhen Ci Yan Jiu,2009,34(2):114-119.
[1]Freeburg PB, Abrahamson DR.Hypoxia-inducible factors and kidney vascular development.Am Soc Nephrol,2003,14:2723-2730.
[2]Yang J,Zhang L,Erbel PJ,et al.Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor.J Biol Chem,2005,280:36047-36054.
[3]Chapman-Smith A,Lutwyche JK,Whitelaw ML.Contribution of the Per/Arnt/Sim(PAS) domains to DNA binding by the basic helix-loop-helix PAS transcriptional regulators.J Biol Chem,2004,279:5353-5362.
[4]Gu YZ,Moran SM,Hogenesch JB,et al.Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit,HIF3alpha.Gene Expr,1998,7(3):205-213.
[5]Goldspink H,David L,PeterM,et al.Sex-related dimorphic response of HIF-la expression in myocardial ischemia.Am J Physiol Heart Circ Physiol,2006;291:957-964.
[6]Lee PJ,Jiang BH,Chin B,et al.Hypoxia-inducible factor 1 mediates transcriptional activation of the hemeoxy genase-1 gene in response to hypoxia.Biol Chem,1997:272(9):5375-5381.
[7]Dery MA,Michaud MD,Richard DE.Hypoxia-inducible factor 1:regulation by hypoxic and non-hypoxic activators.Int J Biochem Cell Biol,2005,37:535-540.
[8]Maxwell PH,Dachs GU,Gleadle JM,et al.Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth.Proc Natl Acad Sci USA,1997,94:8104-8109.
[9]Ingram N,Porter CD.Transcriptional targeting of acute hypoxia in the tumour stroma is a novel and viable strategy for cancer gene therapy.Gene Ther,2005,Jul;12(13):1058-69.
[10]Detwiller KY,Fernando NT,Segal NH,et al.Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A.Cancer Res,2005,65(13):5881-9.
[11]Ferriero DM.Protecting neurons.Epilepsia,2005;46(7):45-51.
[12]Calvert JW,Cahill J,Yamaguchi-Okada M,et al.Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1 alpha and its downstream target genes.J Appl Physiol,2006,101(3):853-65.
[13]Kimbro KS,Simons JW.Hypoxia-inducible factor-1 in human breast and prostate cancer.Endocr Relat Cancer,2006,13(3):739-49.
[14]Sun YJ,Jin KL,Xie L,et al.VEGF induced neuroprotection,neurogenesis,and angiogenesis after focal cerebral isehemia.J Clin Invest,2003,111:1843-51.
[15]Jin KL,Zhu YH,Sun YJ,et al.Vascular endothelial growth factor stimulates neurogenesis in vitro and in vivo.PNAS,2002;99(18):11946-50.
[16]Weda T,Haigh JJ,Ema M,et al.Vascular endothelial growth factor direetly inhibits primitive neural stem cell survival but promotes demitiveneural stem cell survival.J Neurosei,2006;26(25):6803-12.
[17]Wang GL,Jiang BH,Rue EA,et al.Hypoxia-inducible factor-1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.Proc Natl Acad Sci USA,1995,92:5510-5514.
[18]Jeong JW,Bae MK,Ahn MY,et al.Regulation and destabillization of HIF-1 alpha by ARD1-mediated acetylation.Cell,2002,111:709-720.
[19]Yu AY,Frid MG,Shimoda LA,et al.Temporal,spatial,and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol,1998,275:818-26.
[20]Lando D,Peet DJ,Whelan DA,et al.Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.Science,2002,295:858-861.
[21]Lee C,Kim SJ,Jeong DG,et al. Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and yon Hippel-Lindau.J Biol Chem,2003,278:7558-7563.
[22]Jiang BH,Jiang G,Zheng JZ,et al.Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1.Cell Growth Differ,2001,12:363-369.
[23]Stiehl DP,Jelkmann W,Wenger RH,et al.Normoxic induction of the hypoxia-inducible factor 1 alpha by insulin and interleukin-1 beta involves the phosphatidylinositol 3-kinase pathway.FEBS Lett,2002,512:157-162.
[24]Pore N,Jiang Z,Shu HK,et al.Aktl activation can augment hypoxia-inducible factor-1 alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway.Mol Cancer Res,2006,4:471-479.
[25]Ghajar CM,Blevins KS,Huqhes CC,et al.Mesenchymal stem cells enhance angiogenesis in mechanically viable prevascularized tissues via early matrix metallop roteinase up regulation.Tissue Eng,2006,12:2875-2888.
[26]Pugh CW,Ratcliffe PJ.Regulation of angiogenesis by hypoxia-role of the HIF system.Nat Med.2003,9:677-684.
[27]Mazure NM,Brahimi-Horn MC.Pouyssegur J.Protein kinases and the Hypoxia-inducible factor-1,two switches in angiogenesis.Curr Pharm Des,2003,9:531-541.
[28]Belizon A,Balik E,Feingold DL,et al.Major abdominal surgery increases Plasma levels of vascular endothelial growth factor:open more so than minimally invasive methods.Ann Surg,2006,244:792-798.
[29]Blancher C,Moore JW,Talks KL,et al.Relationship of hypoxia-inducible factor(HIF)-lalpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines.Cancer Res,2000,60(24):7106-7113.
[30]Gerber HB,Condorelli F,Park J,et al.Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes.Fit-l,but not Flk-l/KDR,is upregulated by hypoxia.J Biol Chem,1997,272(38):23659-23667.
[31]Liu LX,LU H,Luo Y,et al.Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor.Biochem Bophys Res Commun,2002,291(4):908-914.
[32]BenYosef Y,Lahat N,Shapiro H,et al.Regulation of endothelial matrix metallo proteinase-2 by hypoxia/reoxygenation.Circ Res,2002,90(7):784-791.
[33]Keller M,Yang J,Griesmaier E,et al.Erythropoietin is neuroprotective against NMDA-receptor mediated excitotoxic brain injury in new born mice.Neuro Biol,2006,24(2):357-366.
[34]Wang L,Zhang ZG,Zhang RL,et al.Matrixmetalloproteinase-2(MMP-2) And MMP-9 secreted by erythropoietin activated endothelial cells promote neuroprogenitor cell migration.Neurosci,2006,26(22):5996-6003.
[35]Wang L,Zhang ZQGregg SR,et al.The sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells.J Biol Chem,2007,282(44):32462-32470.
[36]Wang Y,Jin K.VEGF-over expressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration.J Neurosci Res,2007,85(4):740-747.
[37]Jin K,Mao XO,Greenberg DA.Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling.J Neurobiol,2006,66(3):236-242.
[38]De Falco S,Gigante B,Persico MG.Structure and function of placental growth factor.Trends Cardiovac Med.2002,12(6):241-246.
[39]Ferrara M. Vascular endothelial growth factor.Eur J Cancer,1996,32(14):2413-2422.
[40]Ferrara N,Houck K,Jakeman L,et al.Molecular and biological properties of the vascular endothelial growth factor family of protein.Endocr Rev,1992,13(1):18-31.
[41]Persico MG,Vincenti V,DiPalma T,et al.Structure,expression and receptor-binding properties of placenta growth factor(PIGF).Curr Top Microbiol Immunol, 1999,237:31-40.
[42]Houck KA,Ferrara N,Winer J,et al.The vascular endothelial growth factor family identification of a fourth molecular species and characterizacion of alternative splicing of RNA.Mol Endocrinol,1991,5:1806-1814.
[43]Houck KA,Leung DW,Row land AM,et al.Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms.J Biol Chem,1992,167:26031-7.
[44]Poltorak Z,Cohen T,Sivan R,et al.VEGF145,a secreted vascular endothelial cell isoform,that binds to extracellular matrix.J Biol Chem,1997,272:7151-7158.
[45]Park JE,Keller GA,Ferrara N.The vascular endothelial growth factor VEGF isoforms:differential deposition into the subepithelial extra-cellular matrix and bioactivity of extracellular matrixbound VEGF.Mol Biol Cell,1993,4:131.
[46]Keyt BA,Berleau LT,Nguyen HV,et al.The carboxy-terminal domain of vascular endothelial growth factor is critical for its mitogenic potency.J Biol Chem,1996,271:7788-7795.
[47]Miao HQ,Soker S,Feiner L,et al.Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility:functional competition of collapsin-1 and vascular endothelial growth factor 165.J Cell Biol.1999,146:233-242.
[48]Soker S,Takashima S,Miao HQ,et al.Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.Cell,1998,92:735-74.
[49]Vander Geer P,Hunter T,Lindberg RA.Receptor protein Tyrosine kinases and their signal transduction pathways.Annu Rev Cell Biol,1994,10251-10257.
[50]Li QM,Kan FJ,Min Cy.Effect of Weikangning on gastric cancer cell growth and expression of vascular endothelial growth factor and its receptors KDR and Flt-1.World J Gastroenterol,2005,11(7):938-42.
[51]Addya S,Shiroto K,Turoczi T,et al.Ischemic preconditioning mediated cardioprotection is disrupted in heterozygous Flt-1(VEGFR-1) knockout mice.J Mol Cell Cardiol,2005,38(2):345-51.
[52]Kranenburg AR,Boer WI,Alagappan VK,et al.Enhanced bronchial expression of vascular endothelial growth factor and receptors(Flk-1 and Flt-1) in patients with chronic obstructive pulmonary Disease.Thorax,2005,60(2):106-13.
[53]Brown LF,Detmar V,Claffey K,et al.Vasclular permeability factor/vascular endothelial growth factor:a multifunctional angiogenic cytokine.Exs,1997,79:233.
[54]Neufeld GVascular endothelia growth factor and it receptors.Prog Growth Factor Res,1994,5:89-97.
[55]Davis-Smyth T,Chen H,Park J,et al.The second imunologlobulin-like domain of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding and may initiate a signal transduction cascade.EMBO J,1996,15(18):4919-4927.
[56]宋述梅,吴健,寿成超.血管内皮细胞生长因子受体KDR胞外配基结合区单抗对内皮细胞增殖及血管形成的抑制.中华微生物学和免疫学杂志,2000,20(4)：327-330.
[57]马骊,王小宁.人血管内皮生长因子受体配体结合域.生物化学与生物物理学报,2000,32(5)：463-468.
[58]Barleon B,Totzke F,Herzog C,et al.Mapping of sites for ligand binding and receptor dimerization at the extracellular domain of the vascular endothelial growth factor receptor Flt-1.J Biol Chem,1997,272(16):10382-10388.
[59]Hiratsuka S,Maru Y,Okada A,et al.Involvement of Flt-1 tyrosine kinase(vascular endothelial growth factor receptor-1) in pathological angiogenesis.Cancer Res,2001,61:1207-1213.
[60]Carmeliet P.Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.Nat Med,2001,7:575-583.
[61]Robinson CJ,Stringer SE.The splice variants of vascular endothelial growth factor(VEGF) and their receptors.J Cell Sci,2001,114:853-865.
[62]Zeng HY,Zhao DZ,Yang SP,et al.Heterotrimeric G alpha q/G alpha 11 proteins function upstream of vascular endothelial growth factor(VEGF) receptor-2(KDR) phosphorylation in Vascular Permeability Factor/VEGF Signaling.J Bio Chem,2003,278(23):20738-20745.
[63]Carmeliet P,Collen D.Molecular analysis of blood vessel formation and disease.Am J Physiol,1997,237:2091-2104.
[64]Kitsukawa T,Shimizu M,Sanbo M,et al.Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice.Neuron,1997,19:995-1005.
[65]Masahumi Shibuya.Structure of Function of VEGF/VEGF-receptor System Involved in Angiogenesis.Cell Structure And Function.2001(26):25-35.
[66]Dvorak HF,Brown LF,Detmar M,et al.Vascular permeability factor/vascular endothelial growth factor,microvascular hyperpermeability,and angiogenesis.Am J Pathol,1995,146(5):1029-39.
[67]王争.VEGF及其受体基因表达的调控机制.国外医学免疫学分册,2002,25(3)：129-132.
[68]Shweiki D,Itin A,Soffer D,et al.Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.Nature,1992,359(6398):843-5.
[69]Semenza GL.HIF-1 and mechanisms of hypoxia sensing.Curr Opin Cell Biol,2001,13:167-171.
[70]Lyen NV,Kotch LE,Agani F,et al.Cellular and developmental control homeostasis by hypoxia-inducible factor la.Genes Dev,1998,12:149-162.
[71]Freeman RS,Barone MC.Targeting hypoxia-inducible factor(HIF) as a therapeutic strategy for CNS disorders.Curr Drug Targets CNS Neurol Disord,2005,4(1):85-92.
[72]Forsythe JA,Jiang BH,Iyer NV,et al.Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.Mol Cell Biol,1996,16(9):4604-4613.
[73]潘德顺,于江洲,郝天玲,等.Epo,3-端增强子对内皮细胞缺氧时血管内皮生长因子基因转录的影响.同济医科大学学报,1998,27(5)：333-335.
[74]Carmeliet P,Ferreira V,Breier G,et al.Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.Nature,1996,380:435-439.
[75]Levy AP.Levy NA,Wegner S,et al.Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia.J Biol Chem.1995,270:13333-13340.
[76]Levy AP.Levy NS,Goldber MR,et al.Post-transcriptional regulation of vascular endothelial growth factor by hypoxia.J Biol Chem,1995,271(5):2746-2753.
[77]Belizon A,Balik E,Feingold DL,et al.Major abdominal surgery increases plasm a levels of vascular endothelial growth factor:open more so than minimally invasive methods.Ann Surg,2006,244:792-798.
[78]Bartoli M,Gu X,Tsai NT,et al.Vascular endothelial growth factor activiates STAT proteins in arotic endothelial cells.Biol Chem,2000,275(14):33189-33192.
[79]Zhao Y,Neltner BS,Davis HW.Role of MARCKS in regularing endothelial cell proliferation. Am J Physiol,Cell physiol,2000,279(15):1611-1620.
[80]Marti HJ,Bernaudin M,Bellail A,et al.Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia.Am J Pathol,2000,156:965-976.
[81]Yancopoulos GD,Davis S,Gate NW,et al.Vascular-specific growth factors and blood vessel formation.Naure,2000,407:242-247.
[82]Edward MC,Femke Z,Veerle VE,et al.Survivin-Dependent Angiogenesis in Ischemic Brain Molecular Mechanisms of Hypoxia-Induced Up-Regulation.American Journal of Pathology,2003,163(3):935-944.
[83]Tran J,Rak J,Sheehan C,et al.Marked induction of the IAP family antiapoptotic proteins surviving and XIAP by VEGF in vascular endothelial cells.Biochem Biophys Res Commun,1999,264:781-788.
[84]O’Connor DS,Schechner JS,Adida C,et al.Control of apoptosis during angiogenesis by survivin expression in endothelial cells.Am J Pathol,2000,156:393-398.
[85]Chen J,Zhang C,Jiang H,et al.Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice.J Cereb Blood Flow Metab,2005,25(2):281-90.
[86]Ogunshola OO,Stewart WB,Mihalcik V,et al.Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain.Brain Res.2000,119:139-153.
[87]Zhang ZG..Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia.Cereb.Blood Flow Metab.2002,22,379-392.
[88]Marti HJ,Bernaudin M,Bellail A.Hypoxia-Induced Vascular Endothelial Growth Factor Expression Precedes Neovascularization after Cerebral Ischemia.American Journal of Pathology.2000,156:965-976
[89]Krupinski J,Kaluza J,Kumar P,et al.Role of angiogenesis in patients with cerebral ischemic stroke.Stroke 1994,25:1794-1798.
[2]张玉琴,刘诗翔.脑出血的流行病学研究进展.神经损伤与功能重建,2007,2(3)：174-176.
[3]饶明俐.中国脑血管病防治指南.北京：人民卫生出版社,2005：56.
[4]Morgan T,Zuccarello M,Narayan R,et al.Preliminary findings of the minimatly-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial.Aeta Neurochir Suppl,2008,105:147.
[5]Bereczki D,Mihalka L,Szatmari S,et al.Mannitol use in acute stroke:case fatality at 30 days and 1 year.Stroke,2003,34:1730-1735.
[6]吴子辉,吴林.毒为出血性中风至笃之本——三因级联内毒为本.广西中医药,2005,28(1)：49-50.
[7]李富汗.略论血瘀与中风.国医论坛,2003,18(1)：43-44.
[8]Ward NL,Dumont DJ.The angiopoietins and Tie2/Tek:adding to the complexity of cardiovascular development.Semin Cell Dev Biol,2002,13(1):19-27.
[9]Folkman J.Angiogenesis in cancer,vascular,rheumatoid and other disease.Nat Med,1995,1(1):27-31.
[10]Jain RK,Schlenger K,Hockel M,et al.Quantitative angiogenesis assays:progress and problems.Nat Med,1997,3(11):1203-1208.
[11]Gimbrone MA,Leapman SB,Cotran RS,et al.Tumor angiogenesis:iris neovascularization at a distance from experimental intraocular tumors.Natl Cancer Inst.1973,50(1):219-228.
[12]Rafii S,Lyden D,Benezra R,et al.Vascular and haematopoietic stem cells:novel targets for anti-angiogenesis therapy?Nature Rev Cancer.2002,2(11)826-835.
[13]Nobutada M,Ozan Ak,Anthony GD,et al.Electro-Acupuncture at the Zusanli,Yanglingquan,and Kunlun Points Does Not Reduce Anesthetic Requirement.Anesth Analq,2002,95(1):98-102.
[14]Liu XY,Zhou HF,Pan YL,et al.Electro-acupuncture stimulation protects dopaminergic neurons from inflammation-mediated damage in medial forebrain bundle-transected rats.Exp Neurol,2004,189(1):189-196.
[15]Cho NH,Lee JD,Cheong BS,et al.Acupuncture suppresses intrastriatal hemorrhage-induced apoptotic neuronal cell death in rats.Neuroscience Letters,2004,362(2):141-145.
[16]张化彪,黎杏群,张铭湘.脑溢安对脑出血大鼠脑内碱性成纤维生长因子mRNA和肿瘤坏死因子蛋白表达的影响.中国中西医结合杂志,2002,22(7)：518-521.
[17]Tang T,Liu XJ,Zhang ZQ,et al.Cerebral angiogenesis after collagenase-induced intracerebral hemorrhage in rats.Brain Res,2007,1175:134-142.
[18]Rosenberg GA,Mun-Bryce S,Wesley M,et al.Collagenase-induced intracerebral hemorrhage in rats.Stroke,1990,21 (5):801-807.
[19]远山正弥.神经科学尖端技术手册-分子组织化学.北京科学出版社,第一版,1998.
[20]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.Methods,2001,25(4):402-408.
[21]Zhang ZQ,Tang T.Effect of Qi-tonifying and Stasis-eliminating Therapy(益气活血法)on Expression of Vascular Endothelial Growth Factor and Its Receptors Flt-1,Flk-1 in the Brain of Intracerebral Hemorrhagic Rats.Chin J Integr Med,2007,13(4):285-290.
[22]Freeburg PB, Abrahamson DR.Hypoxia-inducible factors and kidney vascular development.Am Soc Nephrol,2003,14:2723-2730.
[23]Zhang ZQZhang L,Tsang W,et al.Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischernia.Cerebral Blood Flow Metab,2002,22(4):379-392.
[24]张化彪,黎杏群,张铭湘.脑溢安对脑出血大鼠脑内碱性成纤维生长因子mRNA和肿瘤坏死因子蛋白表达的影响.中国中西医结合杂志,2002；22(7)：518-521.
[25]Seagroves TN,Peacock DL,Liao D,et al.VHL Deletion Impairs Mammary Alveologenesis But Is Not Sufficient for Mammary Tumorigenesis.Am J Pathol,2010; 175(5):2269-82.
[26]张苏明,唐洲平.脑出血临床研究评价.中华神经科杂志,2003,36：241-242.
[27]刘庆新,苏长海,张苏明.脑出血血肿周围半暗带的病理生理研究进展.国外医学脑血管疾病分册,2002,6：425-427.
[28]Halterman MW,Federoff HJ.HIF-1α and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia.Exp Neurol,1999,159:65-72.
[29]Zhong H,De Marzo AM,Laughner E,et al.Overexpression of hypoxia-inducible factor-alpha in common human cancers and their metastases.Cancer Res,1999,59:5830-5835.
[30]Yu AY,Frid MG,Shimoda LA,et al.Temporal,spatial,and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol,1998,275:L818-L826.
[31]Jiang Y,Wu J,Keep RF,et al.Hypoxia-Inducible Factor-la Accumulation in the Brain After Experimental Intracerebral Hemorrhage.Cerebral Blood Flow Metab,2002;22(6):689-696.
[32]Marti HJ,Bernaudin M,Bellail A,et al.Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischernia.Am J Pathol,2000,156(3):965-976.
[33]Byzova TV,Goldman CK,Jankau J,et al.Adenvirus encoding vascular endothelial growth factor-D induces tissue specific vascular patterns in vivo.Blood,2002,99(12):4434-4442.
[34]刘庆新,张合亮,张苏明.高血压脑出血血肿周围脑组织缺氧诱导因子-1α的表达及意义.中华神经科杂志,2006,39(1)：24-26.
[35]尤艳利,周爽.缺氧诱导因子-1与脑出血的研究进展.中风与神经疾病杂志,2008,25(2)：245-247.
[36]Barnes PM,Powell-Griner E,McFann K,et al.Complementary and alternative medicine use among adults:United States,2002.Advance Data,2004,27(343):1-19.
[37]Haake M,Muller HH,Schade-Brittinger C,et al.German Acupuncture Trials for chronic low back pain:randomized,multicenter,blinded,parallel-group trial with 3 groups.Arch Intern Med,2007,167(17):1892-1898.
[38]Lu PK, Lu GP,Lu DP,et al.Managing acute withdrawal syndrome on patients with heroin and morphine addiction by acupuncture therapy.Acupunct.Electrother. Res,2004,29:187-195.
[39]Ou YW,Han L,Da CD,et al.Influence of acupuncture upon expressing levels of be fibroblast growth factor in rat brain flllowing focal cerebral ischemia-evaluated by time-resolved fluorescence immunoassay.Neurol Res,2001,23(1):47.
[40]Zhang SH,Liu M,Asplund K,et al.Acupuncture for Acute Stroke.Cochrane Database Syst Rev.2005,18(2):1337.34
[41]陈文,顾红卫,马维平,等.针刺足三里、悬钟对缺血性中风患者脑血管功能的影响：多中心随机对照研究.中国针灸,2006,26(12)：851-853.
[42]戚贵明.电针对脑缺血大鼠血清血管内皮生长因子及肿瘤坏死因子的影响：[硕士学位论文].湖北：湖北中医学院,2007.
[43]黑龙江省祖国医药研究所.针灸大成校释.北京：人民卫生出版社,1984,768-770.
[44]韩肖华,黄晓琳,李春芳,等.电针对脑缺血大鼠VEGF及Flk-1表达和细胞外钙离子浓度的影响.中国康复,2003,18(6)：329-331.
[45]Morioka N,Akca O,Doufas AG,et al.Electro-Acupuncture at the Zusanli,Yanglingquan,and Kunlun points does not reduce anesthetic requirement.Anesth Analq,2002;95(1):98-102.
[46]Cai SX,Yu WJ,Zhang L,et al.Effect of electroacupuncture on plasma endogenous endothelial progenitor cell counts in cerebral ischemia-reperfusion rats.Zhen Ci Yan Jiu,2009,34(2):114-119.
[1]Freeburg PB, Abrahamson DR.Hypoxia-inducible factors and kidney vascular development.Am Soc Nephrol,2003,14:2723-2730.
[2]Yang J,Zhang L,Erbel PJ,et al.Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor.J Biol Chem,2005,280:36047-36054.
[3]Chapman-Smith A,Lutwyche JK,Whitelaw ML.Contribution of the Per/Arnt/Sim(PAS) domains to DNA binding by the basic helix-loop-helix PAS transcriptional regulators.J Biol Chem,2004,279:5353-5362.
[4]Gu YZ,Moran SM,Hogenesch JB,et al.Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit,HIF3alpha.Gene Expr,1998,7(3):205-213.
[5]Goldspink H,David L,PeterM,et al.Sex-related dimorphic response of HIF-la expression in myocardial ischemia.Am J Physiol Heart Circ Physiol,2006;291:957-964.
[6]Lee PJ,Jiang BH,Chin B,et al.Hypoxia-inducible factor 1 mediates transcriptional activation of the hemeoxy genase-1 gene in response to hypoxia.Biol Chem,1997:272(9):5375-5381.
[7]Dery MA,Michaud MD,Richard DE.Hypoxia-inducible factor 1:regulation by hypoxic and non-hypoxic activators.Int J Biochem Cell Biol,2005,37:535-540.
[8]Maxwell PH,Dachs GU,Gleadle JM,et al.Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth.Proc Natl Acad Sci USA,1997,94:8104-8109.
[9]Ingram N,Porter CD.Transcriptional targeting of acute hypoxia in the tumour stroma is a novel and viable strategy for cancer gene therapy.Gene Ther,2005,Jul;12(13):1058-69.
[10]Detwiller KY,Fernando NT,Segal NH,et al.Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A.Cancer Res,2005,65(13):5881-9.
[11]Ferriero DM.Protecting neurons.Epilepsia,2005;46(7):45-51.
[12]Calvert JW,Cahill J,Yamaguchi-Okada M,et al.Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1 alpha and its downstream target genes.J Appl Physiol,2006,101(3):853-65.
[13]Kimbro KS,Simons JW.Hypoxia-inducible factor-1 in human breast and prostate cancer.Endocr Relat Cancer,2006,13(3):739-49.
[14]Sun YJ,Jin KL,Xie L,et al.VEGF induced neuroprotection,neurogenesis,and angiogenesis after focal cerebral isehemia.J Clin Invest,2003,111:1843-51.
[15]Jin KL,Zhu YH,Sun YJ,et al.Vascular endothelial growth factor stimulates neurogenesis in vitro and in vivo.PNAS,2002;99(18):11946-50.
[16]Weda T,Haigh JJ,Ema M,et al.Vascular endothelial growth factor direetly inhibits primitive neural stem cell survival but promotes demitiveneural stem cell survival.J Neurosei,2006;26(25):6803-12.
[17]Wang GL,Jiang BH,Rue EA,et al.Hypoxia-inducible factor-1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.Proc Natl Acad Sci USA,1995,92:5510-5514.
[18]Jeong JW,Bae MK,Ahn MY,et al.Regulation and destabillization of HIF-1 alpha by ARD1-mediated acetylation.Cell,2002,111:709-720.
[19]Yu AY,Frid MG,Shimoda LA,et al.Temporal,spatial,and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol,1998,275:818-26.
[20]Lando D,Peet DJ,Whelan DA,et al.Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.Science,2002,295:858-861.
[21]Lee C,Kim SJ,Jeong DG,et al. Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and yon Hippel-Lindau.J Biol Chem,2003,278:7558-7563.
[22]Jiang BH,Jiang G,Zheng JZ,et al.Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1.Cell Growth Differ,2001,12:363-369.
[23]Stiehl DP,Jelkmann W,Wenger RH,et al.Normoxic induction of the hypoxia-inducible factor 1 alpha by insulin and interleukin-1 beta involves the phosphatidylinositol 3-kinase pathway.FEBS Lett,2002,512:157-162.
[24]Pore N,Jiang Z,Shu HK,et al.Aktl activation can augment hypoxia-inducible factor-1 alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway.Mol Cancer Res,2006,4:471-479.
[25]Ghajar CM,Blevins KS,Huqhes CC,et al.Mesenchymal stem cells enhance angiogenesis in mechanically viable prevascularized tissues via early matrix metallop roteinase up regulation.Tissue Eng,2006,12:2875-2888.
[26]Pugh CW,Ratcliffe PJ.Regulation of angiogenesis by hypoxia-role of the HIF system.Nat Med.2003,9:677-684.
[27]Mazure NM,Brahimi-Horn MC.Pouyssegur J.Protein kinases and the Hypoxia-inducible factor-1,two switches in angiogenesis.Curr Pharm Des,2003,9:531-541.
[28]Belizon A,Balik E,Feingold DL,et al.Major abdominal surgery increases Plasma levels of vascular endothelial growth factor:open more so than minimally invasive methods.Ann Surg,2006,244:792-798.
[29]Blancher C,Moore JW,Talks KL,et al.Relationship of hypoxia-inducible factor(HIF)-lalpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines.Cancer Res,2000,60(24):7106-7113.
[30]Gerber HB,Condorelli F,Park J,et al.Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes.Fit-l,but not Flk-l/KDR,is upregulated by hypoxia.J Biol Chem,1997,272(38):23659-23667.
[31]Liu LX,LU H,Luo Y,et al.Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor.Biochem Bophys Res Commun,2002,291(4):908-914.
[32]BenYosef Y,Lahat N,Shapiro H,et al.Regulation of endothelial matrix metallo proteinase-2 by hypoxia/reoxygenation.Circ Res,2002,90(7):784-791.
[33]Keller M,Yang J,Griesmaier E,et al.Erythropoietin is neuroprotective against NMDA-receptor mediated excitotoxic brain injury in new born mice.Neuro Biol,2006,24(2):357-366.
[34]Wang L,Zhang ZG,Zhang RL,et al.Matrixmetalloproteinase-2(MMP-2) And MMP-9 secreted by erythropoietin activated endothelial cells promote neuroprogenitor cell migration.Neurosci,2006,26(22):5996-6003.
[35]Wang L,Zhang ZQGregg SR,et al.The sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells.J Biol Chem,2007,282(44):32462-32470.
[36]Wang Y,Jin K.VEGF-over expressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration.J Neurosci Res,2007,85(4):740-747.
[37]Jin K,Mao XO,Greenberg DA.Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling.J Neurobiol,2006,66(3):236-242.
[38]De Falco S,Gigante B,Persico MG.Structure and function of placental growth factor.Trends Cardiovac Med.2002,12(6):241-246.
[39]Ferrara M. Vascular endothelial growth factor.Eur J Cancer,1996,32(14):2413-2422.
[40]Ferrara N,Houck K,Jakeman L,et al.Molecular and biological properties of the vascular endothelial growth factor family of protein.Endocr Rev,1992,13(1):18-31.
[41]Persico MG,Vincenti V,DiPalma T,et al.Structure,expression and receptor-binding properties of placenta growth factor(PIGF).Curr Top Microbiol Immunol, 1999,237:31-40.
[42]Houck KA,Ferrara N,Winer J,et al.The vascular endothelial growth factor family identification of a fourth molecular species and characterizacion of alternative splicing of RNA.Mol Endocrinol,1991,5:1806-1814.
[43]Houck KA,Leung DW,Row land AM,et al.Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms.J Biol Chem,1992,167:26031-7.
[44]Poltorak Z,Cohen T,Sivan R,et al.VEGF145,a secreted vascular endothelial cell isoform,that binds to extracellular matrix.J Biol Chem,1997,272:7151-7158.
[45]Park JE,Keller GA,Ferrara N.The vascular endothelial growth factor VEGF isoforms:differential deposition into the subepithelial extra-cellular matrix and bioactivity of extracellular matrixbound VEGF.Mol Biol Cell,1993,4:131.
[46]Keyt BA,Berleau LT,Nguyen HV,et al.The carboxy-terminal domain of vascular endothelial growth factor is critical for its mitogenic potency.J Biol Chem,1996,271:7788-7795.
[47]Miao HQ,Soker S,Feiner L,et al.Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility:functional competition of collapsin-1 and vascular endothelial growth factor 165.J Cell Biol.1999,146:233-242.
[48]Soker S,Takashima S,Miao HQ,et al.Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.Cell,1998,92:735-74.
[49]Vander Geer P,Hunter T,Lindberg RA.Receptor protein Tyrosine kinases and their signal transduction pathways.Annu Rev Cell Biol,1994,10251-10257.
[50]Li QM,Kan FJ,Min Cy.Effect of Weikangning on gastric cancer cell growth and expression of vascular endothelial growth factor and its receptors KDR and Flt-1.World J Gastroenterol,2005,11(7):938-42.
[51]Addya S,Shiroto K,Turoczi T,et al.Ischemic preconditioning mediated cardioprotection is disrupted in heterozygous Flt-1(VEGFR-1) knockout mice.J Mol Cell Cardiol,2005,38(2):345-51.
[52]Kranenburg AR,Boer WI,Alagappan VK,et al.Enhanced bronchial expression of vascular endothelial growth factor and receptors(Flk-1 and Flt-1) in patients with chronic obstructive pulmonary Disease.Thorax,2005,60(2):106-13.
[53]Brown LF,Detmar V,Claffey K,et al.Vasclular permeability factor/vascular endothelial growth factor:a multifunctional angiogenic cytokine.Exs,1997,79:233.
[54]Neufeld GVascular endothelia growth factor and it receptors.Prog Growth Factor Res,1994,5:89-97.
[55]Davis-Smyth T,Chen H,Park J,et al.The second imunologlobulin-like domain of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding and may initiate a signal transduction cascade.EMBO J,1996,15(18):4919-4927.
[56]宋述梅,吴健,寿成超.血管内皮细胞生长因子受体KDR胞外配基结合区单抗对内皮细胞增殖及血管形成的抑制.中华微生物学和免疫学杂志,2000,20(4)：327-330.
[57]马骊,王小宁.人血管内皮生长因子受体配体结合域.生物化学与生物物理学报,2000,32(5)：463-468.
[58]Barleon B,Totzke F,Herzog C,et al.Mapping of sites for ligand binding and receptor dimerization at the extracellular domain of the vascular endothelial growth factor receptor Flt-1.J Biol Chem,1997,272(16):10382-10388.
[59]Hiratsuka S,Maru Y,Okada A,et al.Involvement of Flt-1 tyrosine kinase(vascular endothelial growth factor receptor-1) in pathological angiogenesis.Cancer Res,2001,61:1207-1213.
[60]Carmeliet P.Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.Nat Med,2001,7:575-583.
[61]Robinson CJ,Stringer SE.The splice variants of vascular endothelial growth factor(VEGF) and their receptors.J Cell Sci,2001,114:853-865.
[62]Zeng HY,Zhao DZ,Yang SP,et al.Heterotrimeric G alpha q/G alpha 11 proteins function upstream of vascular endothelial growth factor(VEGF) receptor-2(KDR) phosphorylation in Vascular Permeability Factor/VEGF Signaling.J Bio Chem,2003,278(23):20738-20745.
[63]Carmeliet P,Collen D.Molecular analysis of blood vessel formation and disease.Am J Physiol,1997,237:2091-2104.
[64]Kitsukawa T,Shimizu M,Sanbo M,et al.Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice.Neuron,1997,19:995-1005.
[65]Masahumi Shibuya.Structure of Function of VEGF/VEGF-receptor System Involved in Angiogenesis.Cell Structure And Function.2001(26):25-35.
[66]Dvorak HF,Brown LF,Detmar M,et al.Vascular permeability factor/vascular endothelial growth factor,microvascular hyperpermeability,and angiogenesis.Am J Pathol,1995,146(5):1029-39.
[67]王争.VEGF及其受体基因表达的调控机制.国外医学免疫学分册,2002,25(3)：129-132.
[68]Shweiki D,Itin A,Soffer D,et al.Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.Nature,1992,359(6398):843-5.
[69]Semenza GL.HIF-1 and mechanisms of hypoxia sensing.Curr Opin Cell Biol,2001,13:167-171.
[70]Lyen NV,Kotch LE,Agani F,et al.Cellular and developmental control homeostasis by hypoxia-inducible factor la.Genes Dev,1998,12:149-162.
[71]Freeman RS,Barone MC.Targeting hypoxia-inducible factor(HIF) as a therapeutic strategy for CNS disorders.Curr Drug Targets CNS Neurol Disord,2005,4(1):85-92.
[72]Forsythe JA,Jiang BH,Iyer NV,et al.Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.Mol Cell Biol,1996,16(9):4604-4613.
[73]潘德顺,于江洲,郝天玲,等.Epo,3-端增强子对内皮细胞缺氧时血管内皮生长因子基因转录的影响.同济医科大学学报,1998,27(5)：333-335.
[74]Carmeliet P,Ferreira V,Breier G,et al.Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.Nature,1996,380:435-439.
[75]Levy AP.Levy NA,Wegner S,et al.Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia.J Biol Chem.1995,270:13333-13340.
[76]Levy AP.Levy NS,Goldber MR,et al.Post-transcriptional regulation of vascular endothelial growth factor by hypoxia.J Biol Chem,1995,271(5):2746-2753.
[77]Belizon A,Balik E,Feingold DL,et al.Major abdominal surgery increases plasm a levels of vascular endothelial growth factor:open more so than minimally invasive methods.Ann Surg,2006,244:792-798.
[78]Bartoli M,Gu X,Tsai NT,et al.Vascular endothelial growth factor activiates STAT proteins in arotic endothelial cells.Biol Chem,2000,275(14):33189-33192.
[79]Zhao Y,Neltner BS,Davis HW.Role of MARCKS in regularing endothelial cell proliferation. Am J Physiol,Cell physiol,2000,279(15):1611-1620.
[80]Marti HJ,Bernaudin M,Bellail A,et al.Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia.Am J Pathol,2000,156:965-976.
[81]Yancopoulos GD,Davis S,Gate NW,et al.Vascular-specific growth factors and blood vessel formation.Naure,2000,407:242-247.
[82]Edward MC,Femke Z,Veerle VE,et al.Survivin-Dependent Angiogenesis in Ischemic Brain Molecular Mechanisms of Hypoxia-Induced Up-Regulation.American Journal of Pathology,2003,163(3):935-944.
[83]Tran J,Rak J,Sheehan C,et al.Marked induction of the IAP family antiapoptotic proteins surviving and XIAP by VEGF in vascular endothelial cells.Biochem Biophys Res Commun,1999,264:781-788.
[84]O’Connor DS,Schechner JS,Adida C,et al.Control of apoptosis during angiogenesis by survivin expression in endothelial cells.Am J Pathol,2000,156:393-398.
[85]Chen J,Zhang C,Jiang H,et al.Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice.J Cereb Blood Flow Metab,2005,25(2):281-90.
[86]Ogunshola OO,Stewart WB,Mihalcik V,et al.Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain.Brain Res.2000,119:139-153.
[87]Zhang ZG..Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia.Cereb.Blood Flow Metab.2002,22,379-392.
[88]Marti HJ,Bernaudin M,Bellail A.Hypoxia-Induced Vascular Endothelial Growth Factor Expression Precedes Neovascularization after Cerebral Ischemia.American Journal of Pathology.2000,156:965-976
[89]Krupinski J,Kaluza J,Kumar P,et al.Role of angiogenesis in patients with cerebral ischemic stroke.Stroke 1994,25:1794-1798.