HIF-1α、VEGF以及MVD在子痫前期患者中的表达及相关性研究
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摘要
目的:通过探讨缺氧诱导因子1α(HIF-1α),靶基因血管内皮生长因子(VEGF)以及微血管密度(MVD)在子痫前期患者胎盘组织中的表达与胎盘血管病变的关系,研究子痫前期发病机制。方法:采用链酶菌抗生物素蛋白-过氧化物酶连接(SP)法检测早发型,晚发型重度子痫前期患者和正常妊娠妇女(对照组)的胎盘组织中的HIF-1α、VEGF的表达,并计数胎盘微血管密度(MVD)值,并进行相关性分析。结果:(1)子痫前期患者胎盘组织中HIF-1α阳性表达率明显高于正常对照组,差异具有统计学意义(P<0.05),早发型,晚发型子痫前期组HIF-1α与正常对照组相比,差异均有统计学意义(P<0.05),早发型组HIF-1α阳性表达率高于晚发型组,两者比较,差异有统计学意义(P<0.05)。(2)子痫前期患者胎盘组织中VEGF阳性表达率低于正常对照组,两者比较,差异有统计学意义(P<0.05),而早发型组VEGF阳性表达率低于晚发型组,差异亦有统计学意义(P<0.05)。(3)MVD的计数在正常对照组,晚发型子痫前期组,早发型子痫前期组依次递减,子痫前期组与正常对照组比较有统计学差异(P<0.05),而早发型组与晚发型组比较有统计学差异(P<0.05)。(4)子痫前期组患者和正常对照组胎盘中HIF-1α表达与VEGF及MVD值的变化呈显著负相关(r=-0.562,P<0.05;r=-0.622,P<0.05),而VEGF及MVD值的变化呈显著正相关(r=0.718,P<0.05)。结论:HIF-1α在子痫前期患者胎盘组织中表达升高,通过下调靶基因VEGF,引起VEGF降低,影响胎盘血管重铸,参与子痫前期的发生和发展。
Objective:To investigate the expression and correlation of hypoxia-inducible factor -1α(HIF-1α),vascular endothelial growth factor(VEGF)and the microvessel density(MVD)in the preeclampsia placenta,and their relationship with placental vascular ,and discuss their significance in the pathogenesis of preeclampsia. Methods:the expression to HIF-1α,VEGF and MVD were assayed by using SP immunohistochemical method in placentas of the normal pregnant group,early onset severe preeclampsia group and late onset group, the relationship of the HIF-1α,VEGF and MVD was analyzed. Results:(1)the expression of HIF-1αin preeclampsia group obviously increased and was significantly higher than in normal group(P<0.05), in early onset severe preeclampsia group was significantly higher than in late onset groups(P<0.05).(2)VEGF expression obviously reduced in preeclampsia group and was significantly lower than in normal group(P<0.05), in early onset severe preeclampsia group it was lower than in late onset groups(P<0.05).(3)the microvessel density(MVD)reduced in preeclampsia group and was significantly lower than in normal group(P<0.05), in early onset severe preeclampsia group it was lower than in late onset groups(P<0.05).(4)HIF-1αexpression was negatively correlated with the expression of VEGF and MVD(r=-0.562, P<0.05; r=-0.622, P<0.05)in preeclampsia group,and the expression of VEGF was positively correlated with the expression of MVD(r=0.718, P<0.05). Conclusion:Increased HIF-1αexpression in preeclamptic placenta indicates HIF-1αmight be involved in pathogenesis of preeclampsia,possibly through down-regulating VEGF gene transcription and affecting the placental vascular reconstruction.
Objective:To investigate the expression and correlation of hypoxia-inducible factor -1α(HIF-1α),vascular endothelial growth factor(VEGF)and the microvessel density(MVD)in the preeclampsia placenta,and their relationship with placental vascular ,and discuss their significance in the pathogenesis of preeclampsia. Methods:the expression to HIF-1α,VEGF and MVD were assayed by using SP immunohistochemical method in placentas of the normal pregnant group,early onset severe preeclampsia group and late onset group, the relationship of the HIF-1α,VEGF and MVD was analyzed. Results:(1)the expression of HIF-1αin preeclampsia group obviously increased and was significantly higher than in normal group(P<0.05), in early onset severe preeclampsia group was significantly higher than in late onset groups(P<0.05).(2)VEGF expression obviously reduced in preeclampsia group and was significantly lower than in normal group(P<0.05), in early onset severe preeclampsia group it was lower than in late onset groups(P<0.05).(3)the microvessel density(MVD)reduced in preeclampsia group and was significantly lower than in normal group(P<0.05), in early onset severe preeclampsia group it was lower than in late onset groups(P<0.05).(4)HIF-1αexpression was negatively correlated with the expression of VEGF and MVD(r=-0.562, P<0.05; r=-0.622, P<0.05)in preeclampsia group,and the expression of VEGF was positively correlated with the expression of MVD(r=0.718, P<0.05). Conclusion:Increased HIF-1αexpression in preeclamptic placenta indicates HIF-1αmight be involved in pathogenesis of preeclampsia,possibly through down-regulating VEGF gene transcription and affecting the placental vascular reconstruction.
引文
[1] Diagnosis and management of preeclampsia and eclampsia. American College of Obstetricians and Gynecologists(ACOG)Practice Bulletin[J]. No.33. Obstet Gynecol,2002,99:159-167
[2] Carr DB, Mc Donald GB, Brateng D, et al. The relationship between hemodynamics and inflammatory activation in women at risk for preeclampsia. Obstet Gynecol(United states),2001,98(6):1109-1116
[3] Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia[J]. Lancet, 2001,357(9249):53-56
[4]乐杰,主编.妇产科学[M].6版.北京:人民卫生出版社,2004:99-100
[5] Merviel P,Carbillon L,Ch illier JC,et al. Pathophysio logy of preeclampsia:links with implantation disorders[J]. European JObstet Gyneco l Rep rod Bio,2004,115(2):134-147
[6] Semenza GL. Structural and functional analysis of hypoxia-inducible factor-1[J]. Kidney Int,1997,51(2):553-555
[7] Kallio PJ,Wilson WJ,O’Brien S,et al.Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway,Biol Chem,1999, 274:6519-6525
[8] Grundwald M, Avraham I, Dor Y, et al. VEGF-induced adult neovascularization:recruitment,retention,and role of accessory cells[J].Cell,2006, 124(1):18-21
[9]卢俊玲,胡章和.血管内皮生长因子与妊娠期高血压疾病的关系[J].实用妇产科杂志,2002,18(1):14-16
[10]杨孜,李蓉.早发型重度先兆子痫的临床界定及保守治疗探讨[J].中华妇产科杂志,2005,5(40),5:302~305
[11] Tsatsaris V,Goffin F,Munaut C,et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients:pathophysiological consequences[J]. J Clin Endocrinol Metab,2003,88(11):5555-5563
[12] Levine RJ,Maynard SE,Qian C,et al. Circulating angiogenic factors and the risk of preeclampsia[J]. N Engl J Med,2004,350(7):672-683
[13] Zhong H,De Marzo AM,Laughner E et al.Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases[J]. Cancer Res.1999,59(22):5830-5835.
[14] Zhang H,Semenza GL.Up-regulation of Hypoxia-inducible factor-1a is an early event in prostate carcinogenesis[J]. Cancer Deteet Prev,2004,28(2):88-93
[15]王家良,主编.临床流行病学[M].6版.北京:人民卫生出版社,2004:83-84
[16] Stolze IP,Tian YM,Appelhoff RJ.Genetic analysis of the role of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor(HIF)in regulating HIF transcriptional target genes[J]. Biol Chem. 2004,279(41):42719-42725
[17] Ukashev D,Caldwell C,Ohta A,et al.Differential regulation of two altermatively spliced isoform of hypoxio-induciable factor-1 in activated Tlymphocytes[J]. Biol Chem,2001,276:48754-48763
[18] Hayashi M,Sakata M,Takeda T,et al.Hypoxia up-regulates hypoxia-inducible factor-1alpha expression through RhoA activation in trophoblast cells[J]. Clin Endocrinol Metab. 2005 ,90(3):1712-9
[19] Rajakumar A ,Conrad KP. Expression,ontogeny,and regulation of hypoxia- inducible transcription factors in the human placenta[J]. Biol Reprod,2000, 63(2):559-5694
[20] Levine RJ.Maynard SE.Qian C.et al.Circulating angiogenic factors and the risk of preeclampsia[J]. N Engl J Med,2004,350(7):672-683
[21] Dokras A,Hoffmann DS,Eastvold JS. Severe feto-placental abnormalities precede the onset of hypertension and proteinuria in a mouse model of preeclampsia[J]. Biol Reprod. 2006 ,75(6):899-907
[22] Neufeld G,Cohen T,Shraga N,et al. The neuropilins:multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis[J]. Trends Cardiovasc Med,2002,12(1):13-19
[23] Torry DS,Mukherjea D,Arroyo J,et al. Expression and function of placenta growth factor:implications for abnormal placentation[J]. J Soc Gynecol Investig,2003, 10(4):178-188
[24] Maynard SE,Venkatesha S,Thadhani R,et al. Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia[J]. Pediatr Res,2005, 57(5pt 2):1R-7R
[25] Roberts JM,Gammill HS. Preeclampsia:recent insights[J]. Hypertension,2005, 46(6):1243-1249
[26] Ahmad S,Ahmed A. Antiangiogenic effect of soluble vascular endothelial growth factor receptor-1 in placental angiogenesis[J].Endothelium,2005,12(1-2):89-95.
[27] Trollmann R,Amann K,Schoof E,et al. Hypoxia activates the human placental vascular endothelial growth factor system in vitro and in vivo:up-regulation of vascular endothelial growth factor in clinically relevant hypoxic ischemia in birth asphyxia[J]. Am J Obstet Gynecol,2003,188(2):517-523
[28] Belozerov VE,Van Meir EG. Hypoxia inducible factor-1:a noval target for cancer therapy[J]. Anticancer Drugs,2005,16(9):901-909
[29] Sugimoto H,Hamano Y,Charytan D,et al. Neutralization of circulating vascular endothelial growth factor(VEGF)by anti-VEGF antibodies and soluble VEGF receptor 1(sFlt-1)induces proteinuria[J]. J Biol Chem,2003,278(15):12605-12608
[30] Bdolah Y,Karumanchi SA,Sachs BP. Recent advances in understanding of preeclampsia[J]. Croat Med J,2005,46(5):728-736
[31] Sugimoto H,Hamano Y,Charytan D,et al. Neutralization of circulating vascular endothelial growth factor(VEGF)by anti-VEGF antibodies and soluble VEGF receptor 1(sFlt-1)induces proteinuria[J]. J Biol Chem,2003,278(15):12605-12608.
[32] Maharaj AS,D'Amore PA. Roles for VEGF in the adult[J]. Microvasc Res. 2007 , 74(2-3):100-113
[33] Koga K,Osuga Y,Yoshino O et al. Elevated serum soluble vascular endothelial growth factor receptor 1(sVEGFR-1)levels in women with preeclampsia[J]. Clin Endocrinol Metab. 2003,88(5):2348-2351
[34] Bdolah Y,Sukhatme VP,Karumanchi SA. Angiogenic imbalance inthe pathophysiology of preeclampsia:newer insights[J]. SeminNephrol,2004,24(6): 548-556
[1] CarrDB,McDonaldGB,BratengD,etal. The relationship between hemodynamics and inflammatory activation in women at risk for preeclampsia. Obstet Gynecol (United states),2001,98(6):1109-1116
[2] Noris M. Mechanisms of disease :Pre-eclampsia[J]. Nat Clin Pract Nephrol,2005 , 1(2):98-114
[3] Semenza GL. Structural and functional analysis of hypoxia-inducible factor-1[J]. Kidney Int,1997,51(2):553-555
[4] Caniggia I,MostchafiH,Lye SJ,etal. Oxygen and placental devel-opment in the first trimester:implication for the pathophysiology of preeclampsia[J].Placenta,1999, 20(SupplB):5-11
[5] Semenza GL,Wang GL.A nuclear factor inducead by hypoxia via de novo protein syuthesis binds to the human erythropoietin gene enhance at a site required for transcriptional activation .MOL cell Biol,1992,12(12):5447-5448
[6] Semenza GL,Agani F,Booth G,et al.Structual and functional analysis of hypoxia-inducible factor 1.Kidney Zat,1997,51(2):553-554
[7] Calzada MJ,delPesol.Hypoxia-inducible factors and cancer[J]. Clin Transl Oncol, 2007,9(5):278-289
[8] Huang LE,GUJ,Schau M,et al. Regulatation of hypoxia-inducible factor-1 alpha is mediated by an O2–dependant degradation domain via the ubiquitin-proteasome pathway.procnatl Acad Sci USA,1998;95(14):7987-7992
[9] Karen D,Cowden Dahl. Hypoxia-Inducible Factors 1αand 2αRegulate Trophoblast Differentiation[J]. Mol Cell Biol,2005,25(23):10479–10491
[10] Bruick BK,Mcknight SL.A conserved family of proly-4-hydroxy 1ases that modify HIF.Science,2001,294(5545):1337-1340
[11] Semenza GL. Regulation of physiological responses to continuous and intermittent hypoxia by hypoxia-inducible factor 1[J]. Exp Physiol,2006 ,91(5):803-806
[12] Zagzag D,Zhong H,Scalzitti JM,et al·Expression of hypoxia-inducible factor1 alpha in brain tumors:associationwith angiogenesis,invasion,and progression[J]. Cancer, 2000; 88(11):2606-18
[13] Liu Lx,LuH.Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1[J].Biochem Biophys Res Commum,2002;291(4):908-14
[14] Hirota K,Semenza GL . Regulation of angiogenesis by hypoxia-inducible factor[J]. Crit Rev Oncol Hematol. 2006 ,59(1):15-26
[15] Soleymanlou N. Molecular evidence of placental hypoxia in preeclampsia[J]. Clin Endocrinol Metal,2005,90(7):4299-4308
[16]黄莉华,庞战军,邢福祺.早孕和足月滋养细胞中侵袭相关性基因的表达变化[J].细胞与分子免疫学杂志,2003,19(3):302-304
[17] Ietta F. Dynamic HIF1A regulation during human placental development[J]. Biol Reprod,2006 ,75(1):112-121
[18] Cowden Dahl KD,Fryer BH,Mack FA,et al. Hypoxia inducible factors 1alpha and 2alpha regulate trophoblast differentiation[J].Mol Cell Biol,2005,25(23):10479- 10491
[19] Caniggia I,Winter JL .Hypoxia inducible factor-1:oxygen regulation of trophoblast differentiation in normal and pre-eclamptic pregnancies[J].Placenta, 2002,23[Suppl A]:S47-57.
[20] Zhou Y,Genbacev O,Damsky CH,et al. Oxygen regulates human cytotrohpoblast differentiation and invasion: implications for endovas-cular invasion in normalpregnancy and in pre-eclampsia[J].J Reprod Immunol,1998, 39(1-2): 197-213
[21] Rajakumar A,Brandon HM,Daftary A,et al.Evidence for the functional activity of hypoxia-inducible transcription factors overexpressed in preeclamptic placenta[J]. Placenta,2004 ,25(10):763-769
[22] Khetsuriani T,Chabashvili N,Sanikidze T. Role of endothelin-1 and nitric oxide level in pathogenesis preeclampsia[J]. Georgian Med News. 2006,(141):17-21
[23] Ajne G,Ahlborg G,Wolff K et al. Contribution of endogenous endothelin-1 to basal vascular tone during normal pregnancy and preeclampsia. Am J Obstet Gynecol[J]. 2005 ,193(1):234-240
[24] Hu CJ,Wang LY,Chodosh LA ,et a1.Diferential roles of hypoxia-inducible factor 1a(HIF-1α)and HIF-2a in hypoxic gene regulation[J].Mol Cel Biol,2003,23(24): 9361-9374
[25] Spinella F,RosanòL,Di Castro V et al.Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1alpha in human melanoma cells[J]. Cancer Res. 2007 ,67(4):1725-1734.
[26] Gilbert JS,Ryan MJ,LaMarca BB et al. Pathophysiology of hypertension during preeclampsia:linking placental ischemia with endothelial dysfunction[J]. Am JPhysiol Heart Circ Physiol. 2008 ,294(2):H541-550
[27] Slaghekke F,Dekker G,Jeffries B. ndogenous inhibitors of nitric oxide and preeclampsia[J]. J Matern Fetal Neonatal Med. 2006 ,9(8):447-452
[28] Callapina M. NO restores HIF-1αlpha hydroxylation during hypoxia:role of reactive oxygen species[J]. Free Radic Biol Med,2005,39(7):925-936
[29] Brune B,Zhou J.The role of nitric oxide(NO)in stability regulation of Hypoxia-inducible factor-1alpha(HIF-1α)[J].Curr Med Chem,2003,10(10):845-855
[30] Domali E,Messinis IE. Leptin in pregnancy[J]. Matern Fetal Neonatal Med. 2002, 12(4):222-230
[31]胡坤.严亚迎.高英敏et al.妊高征患者血清瘦素水平与血压的相关性研究[J].实用医学杂志,2003 ,19(2): 137
[32] Poston L. Leptin and preeclampsia[J].Semin Reprod Med. 2002 ,20(2):131-138
[33] Trollmann R,Klingmüller K,Schild RL,et al. Differential gene expression of somatotrophic and growth factors in response to in vivo hypoxia in human placenta[J]. Am J Obstet Gynecol,2007,197(6):601.e1-6
[34] Iwagaki S,Yokoyama Y,Tang L,et al. Augmentation of leptin and hypoxia- inducible factor 1alpha mRNAs in the pre-eclamptic placenta[J]. Gynecol Endocrinol[J]. 2004,18(5):263-268
[35] Tipoe GL,Lau TY,Nanji AA,Fung ML. Expression and functions of vasoactive substances regulated by hypoxia-inducible factor-1 in chronic hypoxemia[J]. Cardiovasc Hematol Agents Med Chem. 2006 ,4(3):199-218
[36] Grimshaw MJ. Endothelins and hypoxia-inducible factor in cancer[J].Endocr Relat Cancer. 2007,14(2):233-244
[37] Liu LX,Lu H.Stabilization of vascular endotlelial growth factor Mrna by hypoxia–inducible factor1[J].Biochem Biophys Res Commum,2002,291(4):908-914
[38] Ahmad S,Ahmed A. Antiangiogenic effect of soluble vascular endothelial growth factor receptor-1 in placental angiogenesis[J]. Endothelium,2005,12(1-2):89-95
[39] Rajakumar A,Brandon HM,Daftary A,et al. Evidence for the functional activity of hypoxia-inducible transcription factors overexpressed in preeclamptic placentae[J]. Placenta,2004 ,25(10):763-769
[40] Fowler DJ,Nicolaides KH,Miell JP et al. Insulin-like growth factor binding protein-1(IGFBP-1):a multifunctional role in the human female reproductive tract. Hum Reprod Update[J]. 2000 ,6(5):495-504
[41] Díaz E,Cárdenas M,Ariza AC. Placental insulin and insulin-like growth factor Ireceptors in normal and preeclamptic pregnancies. Clin Biochem[J]. 2005,38(3): 243-247
[42] Slomiany MG,Rosenzweig SA.Hypoxia-inducible factor-1-dependent and -independent regulation of insulin-like growth factor-1-stimulated vascular endothelial growth factor secretion[J].Pharmacol Exp Ther,2006,318(2):666-675
[43] Ning Y,Williams MA,Vadachkoria S et al. Maternal plasma concentrations of insulinlike growth factor-1 and insulinlike growth factor-binding protein-1 in early pregnancy and subsequent risk of preeclampsia[J]. Clin Biochem. 2004,37(11): 968-973
[44] Ingec M,Gursoy HG,Yildiz L et al . Serum levels of insulin,IGF-1,and IGFBP-1 in pre-eclampsia and eclampsia[J]. Int J Gynaecol Obstet. 2004 ,84(3):214-219
[45] Zdravkovic T,Genbacev O,McMaster MT et al. The adverse effects of maternal smoking on the human placenta[J]. Placenta,2005,26[SupplA]:S81-86
[46] Michaud SE,Ménard C,Guy LG et al. Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure:impairment of the HIF-1αlpha/VEGF pathway[J]. FASEB J. 2003 ,17(9):1150-1152
[2] Carr DB, Mc Donald GB, Brateng D, et al. The relationship between hemodynamics and inflammatory activation in women at risk for preeclampsia. Obstet Gynecol(United states),2001,98(6):1109-1116
[3] Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia[J]. Lancet, 2001,357(9249):53-56
[4]乐杰,主编.妇产科学[M].6版.北京:人民卫生出版社,2004:99-100
[5] Merviel P,Carbillon L,Ch illier JC,et al. Pathophysio logy of preeclampsia:links with implantation disorders[J]. European JObstet Gyneco l Rep rod Bio,2004,115(2):134-147
[6] Semenza GL. Structural and functional analysis of hypoxia-inducible factor-1[J]. Kidney Int,1997,51(2):553-555
[7] Kallio PJ,Wilson WJ,O’Brien S,et al.Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway,Biol Chem,1999, 274:6519-6525
[8] Grundwald M, Avraham I, Dor Y, et al. VEGF-induced adult neovascularization:recruitment,retention,and role of accessory cells[J].Cell,2006, 124(1):18-21
[9]卢俊玲,胡章和.血管内皮生长因子与妊娠期高血压疾病的关系[J].实用妇产科杂志,2002,18(1):14-16
[10]杨孜,李蓉.早发型重度先兆子痫的临床界定及保守治疗探讨[J].中华妇产科杂志,2005,5(40),5:302~305
[11] Tsatsaris V,Goffin F,Munaut C,et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients:pathophysiological consequences[J]. J Clin Endocrinol Metab,2003,88(11):5555-5563
[12] Levine RJ,Maynard SE,Qian C,et al. Circulating angiogenic factors and the risk of preeclampsia[J]. N Engl J Med,2004,350(7):672-683
[13] Zhong H,De Marzo AM,Laughner E et al.Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases[J]. Cancer Res.1999,59(22):5830-5835.
[14] Zhang H,Semenza GL.Up-regulation of Hypoxia-inducible factor-1a is an early event in prostate carcinogenesis[J]. Cancer Deteet Prev,2004,28(2):88-93
[15]王家良,主编.临床流行病学[M].6版.北京:人民卫生出版社,2004:83-84
[16] Stolze IP,Tian YM,Appelhoff RJ.Genetic analysis of the role of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor(HIF)in regulating HIF transcriptional target genes[J]. Biol Chem. 2004,279(41):42719-42725
[17] Ukashev D,Caldwell C,Ohta A,et al.Differential regulation of two altermatively spliced isoform of hypoxio-induciable factor-1 in activated Tlymphocytes[J]. Biol Chem,2001,276:48754-48763
[18] Hayashi M,Sakata M,Takeda T,et al.Hypoxia up-regulates hypoxia-inducible factor-1alpha expression through RhoA activation in trophoblast cells[J]. Clin Endocrinol Metab. 2005 ,90(3):1712-9
[19] Rajakumar A ,Conrad KP. Expression,ontogeny,and regulation of hypoxia- inducible transcription factors in the human placenta[J]. Biol Reprod,2000, 63(2):559-5694
[20] Levine RJ.Maynard SE.Qian C.et al.Circulating angiogenic factors and the risk of preeclampsia[J]. N Engl J Med,2004,350(7):672-683
[21] Dokras A,Hoffmann DS,Eastvold JS. Severe feto-placental abnormalities precede the onset of hypertension and proteinuria in a mouse model of preeclampsia[J]. Biol Reprod. 2006 ,75(6):899-907
[22] Neufeld G,Cohen T,Shraga N,et al. The neuropilins:multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis[J]. Trends Cardiovasc Med,2002,12(1):13-19
[23] Torry DS,Mukherjea D,Arroyo J,et al. Expression and function of placenta growth factor:implications for abnormal placentation[J]. J Soc Gynecol Investig,2003, 10(4):178-188
[24] Maynard SE,Venkatesha S,Thadhani R,et al. Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia[J]. Pediatr Res,2005, 57(5pt 2):1R-7R
[25] Roberts JM,Gammill HS. Preeclampsia:recent insights[J]. Hypertension,2005, 46(6):1243-1249
[26] Ahmad S,Ahmed A. Antiangiogenic effect of soluble vascular endothelial growth factor receptor-1 in placental angiogenesis[J].Endothelium,2005,12(1-2):89-95.
[27] Trollmann R,Amann K,Schoof E,et al. Hypoxia activates the human placental vascular endothelial growth factor system in vitro and in vivo:up-regulation of vascular endothelial growth factor in clinically relevant hypoxic ischemia in birth asphyxia[J]. Am J Obstet Gynecol,2003,188(2):517-523
[28] Belozerov VE,Van Meir EG. Hypoxia inducible factor-1:a noval target for cancer therapy[J]. Anticancer Drugs,2005,16(9):901-909
[29] Sugimoto H,Hamano Y,Charytan D,et al. Neutralization of circulating vascular endothelial growth factor(VEGF)by anti-VEGF antibodies and soluble VEGF receptor 1(sFlt-1)induces proteinuria[J]. J Biol Chem,2003,278(15):12605-12608
[30] Bdolah Y,Karumanchi SA,Sachs BP. Recent advances in understanding of preeclampsia[J]. Croat Med J,2005,46(5):728-736
[31] Sugimoto H,Hamano Y,Charytan D,et al. Neutralization of circulating vascular endothelial growth factor(VEGF)by anti-VEGF antibodies and soluble VEGF receptor 1(sFlt-1)induces proteinuria[J]. J Biol Chem,2003,278(15):12605-12608.
[32] Maharaj AS,D'Amore PA. Roles for VEGF in the adult[J]. Microvasc Res. 2007 , 74(2-3):100-113
[33] Koga K,Osuga Y,Yoshino O et al. Elevated serum soluble vascular endothelial growth factor receptor 1(sVEGFR-1)levels in women with preeclampsia[J]. Clin Endocrinol Metab. 2003,88(5):2348-2351
[34] Bdolah Y,Sukhatme VP,Karumanchi SA. Angiogenic imbalance inthe pathophysiology of preeclampsia:newer insights[J]. SeminNephrol,2004,24(6): 548-556
[1] CarrDB,McDonaldGB,BratengD,etal. The relationship between hemodynamics and inflammatory activation in women at risk for preeclampsia. Obstet Gynecol (United states),2001,98(6):1109-1116
[2] Noris M. Mechanisms of disease :Pre-eclampsia[J]. Nat Clin Pract Nephrol,2005 , 1(2):98-114
[3] Semenza GL. Structural and functional analysis of hypoxia-inducible factor-1[J]. Kidney Int,1997,51(2):553-555
[4] Caniggia I,MostchafiH,Lye SJ,etal. Oxygen and placental devel-opment in the first trimester:implication for the pathophysiology of preeclampsia[J].Placenta,1999, 20(SupplB):5-11
[5] Semenza GL,Wang GL.A nuclear factor inducead by hypoxia via de novo protein syuthesis binds to the human erythropoietin gene enhance at a site required for transcriptional activation .MOL cell Biol,1992,12(12):5447-5448
[6] Semenza GL,Agani F,Booth G,et al.Structual and functional analysis of hypoxia-inducible factor 1.Kidney Zat,1997,51(2):553-554
[7] Calzada MJ,delPesol.Hypoxia-inducible factors and cancer[J]. Clin Transl Oncol, 2007,9(5):278-289
[8] Huang LE,GUJ,Schau M,et al. Regulatation of hypoxia-inducible factor-1 alpha is mediated by an O2–dependant degradation domain via the ubiquitin-proteasome pathway.procnatl Acad Sci USA,1998;95(14):7987-7992
[9] Karen D,Cowden Dahl. Hypoxia-Inducible Factors 1αand 2αRegulate Trophoblast Differentiation[J]. Mol Cell Biol,2005,25(23):10479–10491
[10] Bruick BK,Mcknight SL.A conserved family of proly-4-hydroxy 1ases that modify HIF.Science,2001,294(5545):1337-1340
[11] Semenza GL. Regulation of physiological responses to continuous and intermittent hypoxia by hypoxia-inducible factor 1[J]. Exp Physiol,2006 ,91(5):803-806
[12] Zagzag D,Zhong H,Scalzitti JM,et al·Expression of hypoxia-inducible factor1 alpha in brain tumors:associationwith angiogenesis,invasion,and progression[J]. Cancer, 2000; 88(11):2606-18
[13] Liu Lx,LuH.Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1[J].Biochem Biophys Res Commum,2002;291(4):908-14
[14] Hirota K,Semenza GL . Regulation of angiogenesis by hypoxia-inducible factor[J]. Crit Rev Oncol Hematol. 2006 ,59(1):15-26
[15] Soleymanlou N. Molecular evidence of placental hypoxia in preeclampsia[J]. Clin Endocrinol Metal,2005,90(7):4299-4308
[16]黄莉华,庞战军,邢福祺.早孕和足月滋养细胞中侵袭相关性基因的表达变化[J].细胞与分子免疫学杂志,2003,19(3):302-304
[17] Ietta F. Dynamic HIF1A regulation during human placental development[J]. Biol Reprod,2006 ,75(1):112-121
[18] Cowden Dahl KD,Fryer BH,Mack FA,et al. Hypoxia inducible factors 1alpha and 2alpha regulate trophoblast differentiation[J].Mol Cell Biol,2005,25(23):10479- 10491
[19] Caniggia I,Winter JL .Hypoxia inducible factor-1:oxygen regulation of trophoblast differentiation in normal and pre-eclamptic pregnancies[J].Placenta, 2002,23[Suppl A]:S47-57.
[20] Zhou Y,Genbacev O,Damsky CH,et al. Oxygen regulates human cytotrohpoblast differentiation and invasion: implications for endovas-cular invasion in normalpregnancy and in pre-eclampsia[J].J Reprod Immunol,1998, 39(1-2): 197-213
[21] Rajakumar A,Brandon HM,Daftary A,et al.Evidence for the functional activity of hypoxia-inducible transcription factors overexpressed in preeclamptic placenta[J]. Placenta,2004 ,25(10):763-769
[22] Khetsuriani T,Chabashvili N,Sanikidze T. Role of endothelin-1 and nitric oxide level in pathogenesis preeclampsia[J]. Georgian Med News. 2006,(141):17-21
[23] Ajne G,Ahlborg G,Wolff K et al. Contribution of endogenous endothelin-1 to basal vascular tone during normal pregnancy and preeclampsia. Am J Obstet Gynecol[J]. 2005 ,193(1):234-240
[24] Hu CJ,Wang LY,Chodosh LA ,et a1.Diferential roles of hypoxia-inducible factor 1a(HIF-1α)and HIF-2a in hypoxic gene regulation[J].Mol Cel Biol,2003,23(24): 9361-9374
[25] Spinella F,RosanòL,Di Castro V et al.Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1alpha in human melanoma cells[J]. Cancer Res. 2007 ,67(4):1725-1734.
[26] Gilbert JS,Ryan MJ,LaMarca BB et al. Pathophysiology of hypertension during preeclampsia:linking placental ischemia with endothelial dysfunction[J]. Am JPhysiol Heart Circ Physiol. 2008 ,294(2):H541-550
[27] Slaghekke F,Dekker G,Jeffries B. ndogenous inhibitors of nitric oxide and preeclampsia[J]. J Matern Fetal Neonatal Med. 2006 ,9(8):447-452
[28] Callapina M. NO restores HIF-1αlpha hydroxylation during hypoxia:role of reactive oxygen species[J]. Free Radic Biol Med,2005,39(7):925-936
[29] Brune B,Zhou J.The role of nitric oxide(NO)in stability regulation of Hypoxia-inducible factor-1alpha(HIF-1α)[J].Curr Med Chem,2003,10(10):845-855
[30] Domali E,Messinis IE. Leptin in pregnancy[J]. Matern Fetal Neonatal Med. 2002, 12(4):222-230
[31]胡坤.严亚迎.高英敏et al.妊高征患者血清瘦素水平与血压的相关性研究[J].实用医学杂志,2003 ,19(2): 137
[32] Poston L. Leptin and preeclampsia[J].Semin Reprod Med. 2002 ,20(2):131-138
[33] Trollmann R,Klingmüller K,Schild RL,et al. Differential gene expression of somatotrophic and growth factors in response to in vivo hypoxia in human placenta[J]. Am J Obstet Gynecol,2007,197(6):601.e1-6
[34] Iwagaki S,Yokoyama Y,Tang L,et al. Augmentation of leptin and hypoxia- inducible factor 1alpha mRNAs in the pre-eclamptic placenta[J]. Gynecol Endocrinol[J]. 2004,18(5):263-268
[35] Tipoe GL,Lau TY,Nanji AA,Fung ML. Expression and functions of vasoactive substances regulated by hypoxia-inducible factor-1 in chronic hypoxemia[J]. Cardiovasc Hematol Agents Med Chem. 2006 ,4(3):199-218
[36] Grimshaw MJ. Endothelins and hypoxia-inducible factor in cancer[J].Endocr Relat Cancer. 2007,14(2):233-244
[37] Liu LX,Lu H.Stabilization of vascular endotlelial growth factor Mrna by hypoxia–inducible factor1[J].Biochem Biophys Res Commum,2002,291(4):908-914
[38] Ahmad S,Ahmed A. Antiangiogenic effect of soluble vascular endothelial growth factor receptor-1 in placental angiogenesis[J]. Endothelium,2005,12(1-2):89-95
[39] Rajakumar A,Brandon HM,Daftary A,et al. Evidence for the functional activity of hypoxia-inducible transcription factors overexpressed in preeclamptic placentae[J]. Placenta,2004 ,25(10):763-769
[40] Fowler DJ,Nicolaides KH,Miell JP et al. Insulin-like growth factor binding protein-1(IGFBP-1):a multifunctional role in the human female reproductive tract. Hum Reprod Update[J]. 2000 ,6(5):495-504
[41] Díaz E,Cárdenas M,Ariza AC. Placental insulin and insulin-like growth factor Ireceptors in normal and preeclamptic pregnancies. Clin Biochem[J]. 2005,38(3): 243-247
[42] Slomiany MG,Rosenzweig SA.Hypoxia-inducible factor-1-dependent and -independent regulation of insulin-like growth factor-1-stimulated vascular endothelial growth factor secretion[J].Pharmacol Exp Ther,2006,318(2):666-675
[43] Ning Y,Williams MA,Vadachkoria S et al. Maternal plasma concentrations of insulinlike growth factor-1 and insulinlike growth factor-binding protein-1 in early pregnancy and subsequent risk of preeclampsia[J]. Clin Biochem. 2004,37(11): 968-973
[44] Ingec M,Gursoy HG,Yildiz L et al . Serum levels of insulin,IGF-1,and IGFBP-1 in pre-eclampsia and eclampsia[J]. Int J Gynaecol Obstet. 2004 ,84(3):214-219
[45] Zdravkovic T,Genbacev O,McMaster MT et al. The adverse effects of maternal smoking on the human placenta[J]. Placenta,2005,26[SupplA]:S81-86
[46] Michaud SE,Ménard C,Guy LG et al. Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure:impairment of the HIF-1αlpha/VEGF pathway[J]. FASEB J. 2003 ,17(9):1150-1152