症状性子宫肌瘤子宫内膜COX-2、VEGF、微血管密度的表达
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摘要
目的:子宫肌瘤是女性生殖器最常见的良性肿瘤,也是人体最常见的肿瘤,常见症状为月经紊乱。在临床工作中发现,有部分患者出现严重子宫异常出血,且该症状出现早晚以及严重程度与子宫肌瘤的大小、肌瘤所在部位无必然联系,甚至部分患者在行子宫肌瘤挖除术后症状仍不缓解,对症治疗效果不佳。推测子宫异常出血与子宫肌瘤患者子宫内膜微环境的改变有关,这种改变是月经紊乱的主要原因。月经的调控有赖于血管舒缩功能和凝血功能的正常发挥,而前者又有赖于月经后子宫内膜重建过程中血管形成的质和量。COX-2和VEGF作为强有力的血管生成调节因子,对月经后子宫内膜重建过程中血管形成的质和量起重要的调控作用。目前有关COX-2和VEGF的研究主要集中在与肿瘤的发生发展的关系上,而COX-2和VEGF在子宫肌瘤子宫内膜血管形成作用的研究未见报道。微血管密度被认为是最理想的衡量血管生成的量化指标。目前国内外未见报道关于COX-2、VEGF和微血管密度在子宫肌瘤子宫内膜中的表达。本实验通过测定子宫肌瘤子宫内膜中COX-2、VEGF和微血管密度的表达,来探讨症状性子宫肌瘤子宫内膜内环境的变化、变化程度以及与子宫肌瘤异常子宫出血的相关性。
方法:选择病理证实为单纯子宫肌瘤标本53例,根据子宫肌瘤患者有无月经改变症状分为A、B两组,C组以月经正常的健康妇女子宫内膜作为正常对照,各组再根据子宫内膜病理类型进行组内分型。A组:症状性子宫肌瘤33例,其中增生期13例、分泌期11例、单纯性增生过长6例、复杂性增生过长3例;B组:无症性子宫肌瘤20例,其中增生期12例、分泌期8例。C组:正常子宫内膜作为对照组共12例,其中增生期6例、分泌期6例。采用免疫组化技术对三组子宫内膜中COX-2、VEGF、MVD进行检测,结果判断标准:标本组织细胞浆或核周有黄色染色为阳性,结果判定采用北京航空航天大学彩色病理图像分析系统计算阳性细胞的扫描面积,采用平均光密度代表各项指标的表达强度。统计学处理使用SPSS12.0统计软件包进行统计学处理,其中VEGF、COX-2、微血管密度结果采用均数±标准差(x|-±s)进行描述,组间及组内比较采用单因素方差分析,VEGF、COX-2、微血管密度相关性用Pearson correlation相关分析,以α=0.05作为差异显著性水准。
结果:
1.VEGF、COX-2在各组子宫内膜中的表达:COX-2、VEGF在A、B、C三组子宫内膜中均有表达,主要表达在腺上皮的细胞浆,少量表达在间质的细胞浆,部分子宫内膜血管内皮细胞可见阳性分布。COX-2、VEGF在A组子宫内膜增生期、分泌期中的表达水平高于B、C两组同型子宫内膜,差异有显著性(P<0.05);在A组单纯性增生过长和复杂性增生过长子宫内膜中的表达水平显著低于A、B、C三组增生期内膜,差异有显著性(P<0.001)。在B组与C组同型子宫内膜中的表达水平,差异无显著性(P>0.05)。A、B、C三组内COX-2、VEGF在增生期的表达水平与分泌期比较,差异均无显著性(P>0.05)。
2.MVD在各组子宫内膜中的表达:CD34阳性细胞计数的MVD在A组增生期和分泌期子宫内膜高于B、C两组同型子宫内膜,差异有显著性(P<0.05),在A组单纯增生过长和复杂增生过长内膜MVD计数近似但又低于A、B、C三组增生期子宫内膜,差异有显著性(P<0.001)。在B组与C组同型子宫内膜中的表达水平,差异无显著性(P>0.05)。A、B、C三组内MVD在增生期的表达水平与分泌期比较,差异均无显著性(P>0.05)。
3.症状性子宫肌瘤子宫内膜中COX-2、VEGF和MVD表达水平的相关性:症状性子宫肌瘤子宫内膜中COX-2与VEGF表达水平均呈正相关(r=0.779,P<0.05;r=0.626,P<0.05;r=0.666,P<0.01),且MVD表达水平与COX-2、VEGF表达水平呈正相关(r=0.829,P<0.05;r=0.798,P<0.05)。
结论:症状性子宫肌瘤子宫内膜COX-2、VEGF和MVD的表达增强,特别是在单纯增生过长和复杂性增生过长的子宫内膜中COX-2、VEGF、MVD均有显著的变化;但无症状性子宫肌瘤子宫内膜内环境无异常改变。本文认为子宫内膜微环境的异常改变是子宫肌瘤患者产生异常子宫出血的原因。这一结论为临床症状性子宫肌瘤患者的保守治疗提供了可靠的理论依据。
Objective: The control of normal menstruation rely on normal function of blood vessel and coagulation, while the function of blood vessel rely on the quality and quantity of the vessel in the course of reconstruction of the endometrium. Vascular endothelial growth factor(VEGF)is the main factor of regulating vascular growth in physiological and pathological situation. VEGF is ascribed with a variety of biological effects including increasing the permeability of capillaries, stimulating mitogenesis and proliferation of endothelial cells and then inducing angiogenesis. Cyclooxygenase is one of the rate-limiting enzymes in the synthesis of PGs in metabolism of arachidonic acid. COX-2 ,as one of the theisoforms, together with VEGF are the angiogenisis activators which have been paid more attention to in recent years. As the main factor of regulating vascular growth, COX-2 and VEGF play an important role in controling the quality and quantity of vascular in the course of reconstrction of the endometrium.Microvessel density(MVD)is regarded as the ideal index in judging the quantity of the blood vessel.This experiment is aimed at exploring the changes of endometrial microenvironment in patients with uterine leiomyomas and to seek a kind of conservative treatment theoretically for patients with sympotomatic uterine leiomyomas by investigating the expressions of VEGF、COX-2 and MVD in endometrium of patients with uterine leiomyomas.
Methods: 53 patients with uterine leiomyomas according to pathological examination were divided into two groups (groupA and group B) based on the symptom of menorrhagia and healthy women with normal menstruation were recruited into group C as healthy controls.Each group were divided into different subgroups according to pathological examination of the endometrium.33 patients with sympotomatic uterine leiomyomas in group A consisted of 13 patients with proliferative phase endometrium, 11 patients with secretory phase endometrium, 6 patients with simple hyperplasia and 3 patients with complex hyperplasia. 20 patients with asympotomatic uterine leiomyomas were recruited into group B with 15 with proliferative phase and 11 with secretory phase. 12 healthy women of group C as healthy controls were consist of 6 with the proliferative phase and 6 with the secretory phase. Immunohistochemistry was used to investigate the expression of COX-2、VEGF、MVD in the endometrium of the three groups. Result-judging criterion was that pale brown dyeing in cellular serosa or nuclei was defined as positive reaction. Immunoreactivity was measured with a computerized image analysis system in a quantitative manner. Acquired data were analysed by SPSS 12.0 statistical software. The date of COX-2、VEGF and MVD in each group were described by x|-±s and compared by One-Way ANOVA. Correlations of COX-2, VEGF and MVD were analysed by Pearson correlation.It is considered to be significant at a probability value of less than 0.05.
Results: The expression of COX-2 and VEGF protein in endometrium of each group: COX-2 and VEGF protein were expressed in three groups,which were expressed predominnatly in the glandular epithelial cell serosa and weakly in stromal cells.There were some expression in vascular endothelial cells.The expression of COX-2 protein and VEGF protein in endometrium of proliefrative and secretory phase in group A was higher than that in group B and C (P<0.05). The expression in endometrium of simple hyperplasia and complex hyperplasia phase was significantly lower than that of the proliefrative phase in each group (P<0.001).There were no significnatly dieffrence in the expression of COX-2 and VEGF between group B and C in the endometrium of proliefrative phase or secretory phase (P>0.05). There were no significnatly dieffrence in the expression of COX-2 and VEGF in the three groups with the endometrium of proliefrative phase or secretory phase (P>0.05).
The expression of MVD in endometrium of each group: The positive expression of CD34-marked MVD in endometrium of proliefrative and secretory phase in group A was significantly higher than that of group B and C (P<0.05). The expression in endometrium of simple hyperplasia and complex hyperplasia phase were similar but significantly lower than that of the proliefrative phase in each group (P<0.001). There were no significnatly difference in the expression of MVD between group B and C in the endometrium of proliefrative phase or secretory phase (P>0.05). There were no significnatly dieffrence in the three groups with the endometrium of proliefrative phase or secretory phase (P>0.05).
Correlations of VEGF、COX-2 and MVD expressions in group A: In all the subgroups, the expression of COX-2 was positively correlated with that of VEGF (r=0.779,P<0.05;r=0.626 , P<0.05,r=0.666 , P<0.01). The expression of MVD was positively correlated with COX-2 and VEGF (r=0.829,P<0.05;r=0.798,P<0.05).
Conclusion: There were increasing expression of COX-2、VEGF and MVD in the endometrium of patients with sympotomatic uterine leiomyomas ,especially in hyperplasia endometrium, but no changes in the endometrium of patients with asympotomatic uterine leiomyomas. Abnormal changes of endomertrial microenvironment is responsible for menorrhagia of patients with uterine leiomyomas.This conclusion provided a reliable theoretical proof of conservative treatment of patients with sympotomatic uterine leiomyomas.
方法:选择病理证实为单纯子宫肌瘤标本53例,根据子宫肌瘤患者有无月经改变症状分为A、B两组,C组以月经正常的健康妇女子宫内膜作为正常对照,各组再根据子宫内膜病理类型进行组内分型。A组:症状性子宫肌瘤33例,其中增生期13例、分泌期11例、单纯性增生过长6例、复杂性增生过长3例;B组:无症性子宫肌瘤20例,其中增生期12例、分泌期8例。C组:正常子宫内膜作为对照组共12例,其中增生期6例、分泌期6例。采用免疫组化技术对三组子宫内膜中COX-2、VEGF、MVD进行检测,结果判断标准:标本组织细胞浆或核周有黄色染色为阳性,结果判定采用北京航空航天大学彩色病理图像分析系统计算阳性细胞的扫描面积,采用平均光密度代表各项指标的表达强度。统计学处理使用SPSS12.0统计软件包进行统计学处理,其中VEGF、COX-2、微血管密度结果采用均数±标准差(x|-±s)进行描述,组间及组内比较采用单因素方差分析,VEGF、COX-2、微血管密度相关性用Pearson correlation相关分析,以α=0.05作为差异显著性水准。
结果:
1.VEGF、COX-2在各组子宫内膜中的表达:COX-2、VEGF在A、B、C三组子宫内膜中均有表达,主要表达在腺上皮的细胞浆,少量表达在间质的细胞浆,部分子宫内膜血管内皮细胞可见阳性分布。COX-2、VEGF在A组子宫内膜增生期、分泌期中的表达水平高于B、C两组同型子宫内膜,差异有显著性(P<0.05);在A组单纯性增生过长和复杂性增生过长子宫内膜中的表达水平显著低于A、B、C三组增生期内膜,差异有显著性(P<0.001)。在B组与C组同型子宫内膜中的表达水平,差异无显著性(P>0.05)。A、B、C三组内COX-2、VEGF在增生期的表达水平与分泌期比较,差异均无显著性(P>0.05)。
2.MVD在各组子宫内膜中的表达:CD34阳性细胞计数的MVD在A组增生期和分泌期子宫内膜高于B、C两组同型子宫内膜,差异有显著性(P<0.05),在A组单纯增生过长和复杂增生过长内膜MVD计数近似但又低于A、B、C三组增生期子宫内膜,差异有显著性(P<0.001)。在B组与C组同型子宫内膜中的表达水平,差异无显著性(P>0.05)。A、B、C三组内MVD在增生期的表达水平与分泌期比较,差异均无显著性(P>0.05)。
3.症状性子宫肌瘤子宫内膜中COX-2、VEGF和MVD表达水平的相关性:症状性子宫肌瘤子宫内膜中COX-2与VEGF表达水平均呈正相关(r=0.779,P<0.05;r=0.626,P<0.05;r=0.666,P<0.01),且MVD表达水平与COX-2、VEGF表达水平呈正相关(r=0.829,P<0.05;r=0.798,P<0.05)。
结论:症状性子宫肌瘤子宫内膜COX-2、VEGF和MVD的表达增强,特别是在单纯增生过长和复杂性增生过长的子宫内膜中COX-2、VEGF、MVD均有显著的变化;但无症状性子宫肌瘤子宫内膜内环境无异常改变。本文认为子宫内膜微环境的异常改变是子宫肌瘤患者产生异常子宫出血的原因。这一结论为临床症状性子宫肌瘤患者的保守治疗提供了可靠的理论依据。
Objective: The control of normal menstruation rely on normal function of blood vessel and coagulation, while the function of blood vessel rely on the quality and quantity of the vessel in the course of reconstruction of the endometrium. Vascular endothelial growth factor(VEGF)is the main factor of regulating vascular growth in physiological and pathological situation. VEGF is ascribed with a variety of biological effects including increasing the permeability of capillaries, stimulating mitogenesis and proliferation of endothelial cells and then inducing angiogenesis. Cyclooxygenase is one of the rate-limiting enzymes in the synthesis of PGs in metabolism of arachidonic acid. COX-2 ,as one of the theisoforms, together with VEGF are the angiogenisis activators which have been paid more attention to in recent years. As the main factor of regulating vascular growth, COX-2 and VEGF play an important role in controling the quality and quantity of vascular in the course of reconstrction of the endometrium.Microvessel density(MVD)is regarded as the ideal index in judging the quantity of the blood vessel.This experiment is aimed at exploring the changes of endometrial microenvironment in patients with uterine leiomyomas and to seek a kind of conservative treatment theoretically for patients with sympotomatic uterine leiomyomas by investigating the expressions of VEGF、COX-2 and MVD in endometrium of patients with uterine leiomyomas.
Methods: 53 patients with uterine leiomyomas according to pathological examination were divided into two groups (groupA and group B) based on the symptom of menorrhagia and healthy women with normal menstruation were recruited into group C as healthy controls.Each group were divided into different subgroups according to pathological examination of the endometrium.33 patients with sympotomatic uterine leiomyomas in group A consisted of 13 patients with proliferative phase endometrium, 11 patients with secretory phase endometrium, 6 patients with simple hyperplasia and 3 patients with complex hyperplasia. 20 patients with asympotomatic uterine leiomyomas were recruited into group B with 15 with proliferative phase and 11 with secretory phase. 12 healthy women of group C as healthy controls were consist of 6 with the proliferative phase and 6 with the secretory phase. Immunohistochemistry was used to investigate the expression of COX-2、VEGF、MVD in the endometrium of the three groups. Result-judging criterion was that pale brown dyeing in cellular serosa or nuclei was defined as positive reaction. Immunoreactivity was measured with a computerized image analysis system in a quantitative manner. Acquired data were analysed by SPSS 12.0 statistical software. The date of COX-2、VEGF and MVD in each group were described by x|-±s and compared by One-Way ANOVA. Correlations of COX-2, VEGF and MVD were analysed by Pearson correlation.It is considered to be significant at a probability value of less than 0.05.
Results: The expression of COX-2 and VEGF protein in endometrium of each group: COX-2 and VEGF protein were expressed in three groups,which were expressed predominnatly in the glandular epithelial cell serosa and weakly in stromal cells.There were some expression in vascular endothelial cells.The expression of COX-2 protein and VEGF protein in endometrium of proliefrative and secretory phase in group A was higher than that in group B and C (P<0.05). The expression in endometrium of simple hyperplasia and complex hyperplasia phase was significantly lower than that of the proliefrative phase in each group (P<0.001).There were no significnatly dieffrence in the expression of COX-2 and VEGF between group B and C in the endometrium of proliefrative phase or secretory phase (P>0.05). There were no significnatly dieffrence in the expression of COX-2 and VEGF in the three groups with the endometrium of proliefrative phase or secretory phase (P>0.05).
The expression of MVD in endometrium of each group: The positive expression of CD34-marked MVD in endometrium of proliefrative and secretory phase in group A was significantly higher than that of group B and C (P<0.05). The expression in endometrium of simple hyperplasia and complex hyperplasia phase were similar but significantly lower than that of the proliefrative phase in each group (P<0.001). There were no significnatly difference in the expression of MVD between group B and C in the endometrium of proliefrative phase or secretory phase (P>0.05). There were no significnatly dieffrence in the three groups with the endometrium of proliefrative phase or secretory phase (P>0.05).
Correlations of VEGF、COX-2 and MVD expressions in group A: In all the subgroups, the expression of COX-2 was positively correlated with that of VEGF (r=0.779,P<0.05;r=0.626 , P<0.05,r=0.666 , P<0.01). The expression of MVD was positively correlated with COX-2 and VEGF (r=0.829,P<0.05;r=0.798,P<0.05).
Conclusion: There were increasing expression of COX-2、VEGF and MVD in the endometrium of patients with sympotomatic uterine leiomyomas ,especially in hyperplasia endometrium, but no changes in the endometrium of patients with asympotomatic uterine leiomyomas. Abnormal changes of endomertrial microenvironment is responsible for menorrhagia of patients with uterine leiomyomas.This conclusion provided a reliable theoretical proof of conservative treatment of patients with sympotomatic uterine leiomyomas.
引文
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35 Ancelin M, Buteau-Lozano H, Meduri G, et al.A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF 189 regulates angiogenesis and vascular permeaility in human uterus [J].Proc Natl Acad Sci USA,2002,9(9):6023~6028
36 Mestre JR,Maekrell PJ,Rivadeneira DE. Redundancy in the signaling pathways and promoter elements regulating cyelooxygenase-2 gene expression in endotoxin-treated macrophage/monocytic cells. J Biol Chem.,2001: 276(6): 3977~82
37 Majima M, Isono M, Zkeda Y, et al.Significant roles of inducible cyclooxygenase (COX)-2 in angiogenesis in rat sponge implants [J]. Jpn J Pharmacol, 1997, 75: 105~114
38 Liu XH, Kirschenbaum A,Yao S, et al.Upregulation of vascular endothelial growth factor by cobalt chloride- simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line[J].Clin Exp Metastasis,1999,17:687~694
1 Folkman J.Seminars in medicine of the Beth Isarel Hospital, Boston.Clinical applications of research on angiogenesis.N Engl J Med 1995;333:1757~1763
2 Nakamura M, Abe Y and Tokunaga T. Pathological significance of vascular endothelial growth factor isoform expression in human cancer.Pathology international 2002; 2: 331~339
3 Ferrara N,Gerber HP, Le Couter J.The biology of VEGF and its receptors.Nat Med, 2003, 9(6): 669~676
4 Taylor RN,Lebovic DI,Hornung D.Endocrine and paracrine regulation of endometrial angiogenesis.Am NY Acad Sci,2001,943:109~121
5 Maas JW, Groothuis PG, Dunselman GA. Endometrial angiogenesis throughout the human menstrual cycle. Hum Reprod ,2001,16(8):1557~1561
6 Takahashi T, Shibuya M. the 230 kDa mature form of KDR/Flk-1(VEGF receptor-2)activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts.Oncogene 1997;14:2079~2089
7 Shirfen JL,Tseng JF,ferrara N.Ovarian steroid regulation of Vaseular endohtelial growth factor in human endometrium.J Clin Endometrinol Metab 1996; 81(8):3112~5
8 Barroso G,Barriouevo M,Rao P.Vaseular endohtelial growth factor,nitricoxde,andlept in follicular fluid levels correlatenegatively with embyro quality in IVF patients. Fert Ster,1999:72(6)
9 MollerB , LindblomB , Olovsson M.ExPerssion of the vascular Endothelial growth factors B and C and their receptors in Human endometrium during the menstrual cycle.Acta Obstet Gynecol Scand.2002Sep; 81(9):817~824
10 Gargett CE,Rogers PA. Human endometrial angiogenesis. Reproduction.2001 Feb; 121(2):181~186
11 Mueller MD, Lebovic DI, Garrett E,et al.Neutrophils infiltrating the endometrium express vascular endothelial growth factor :potential role in endothelial angiogenesis. Fertil Steril,2000,74(1):107~112
12 Kawano Y, Nakamura S,Nasu K,et al.The effect of epidermal growth factor on vascular endothelial growth factor secretion by endometrial stromal cells[J].Clin Exp Med,2002,2(2):69~75
13 Ancelin M, Buteau-Lozano H,Meduri G,et al.A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF 189 regulates angiogenesis and vascular permeaility in human uterus [J]. Proc Natl Acad Sci USA, 2002,9(9):6023~6028
14 Maynard SE, Min JY, Merchan J, et al. Excess placental solute fmslike tyrosine kinase 1 (sFlt-1) may contribute to endothelial dysfunction hypertension and proteinuria in preeclampsia. J Clin Invest, 2003, 111(5):649~658
15 Malik S,Day K,Perrault I,et al.Reduced levels of VEGF-Aand MMP-2 and MMP-9 activity and increased TNF in menstrual endometrium and efficient in women with menorrhagia.Hum Reprod,2006,25(3):896~901
16 Meduri G,Bausero P,Penot-Applanut M.Expression of vascular endothelial growth factor receptors in the human endometrium modulation during the menstrual cycle.Biol Reprod,2000,62(21):439~447
17 Pan JF, Yu YL,Wang Lj et al.The morphologic changes of endometrial spiral arterioales in IUD-induced menorrhagia. Adv Contracep,1994;10:213~222
18 沈铿,楼伟珍.环氧合酶和妇科肿瘤.沈铿,朗景和. 主编.人民卫生出版社.2002, 283~290
19 Hla T., Neilson K.Human cyclooxygenase-2 cDNA. Proc. Nat. Acad. Sci.,1992,89:7384~7388
20 Jones D.A.,Carlton D.P.,Mclntyre T.,et al. Molecular cloning of human prostaglandin endoperoxide synthase typeII and demonstration of expression in response to cytokines.J.Biol.Chem.,1993,268:9049~9054
21 Kraemer S.A.,Meade E.A.,Dewitt D.L. Prostaglandin endoperoxide synthase gene structure: identification of the transcriptional start site and 5-prime-flanking regulatory sequences.Arch.Biochem.BioPhys.,1992,293:391~400
22 Tazawa R., Xu X.-M.,Wu K.K.,et al.Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene.Biochem. Biophys. Res. Commun.,1994,203:190~199
23 Howe LR, Dannenberg AJ. A zole for cyclooxygenase-2 inhibitors in the prevention and treatment of cancer. Semin Oncol, 2002, 29:111~119
24 Morita I,Schindler M,Regier MK,et al. Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2. J Biol Chem.,1995,270:10902~10908
25 Lindsey K, Jager AK, Raidoo DM, et al.Screening of plants used by Southern African traditional healers in the treatment of dysmenorrhoea for prostaglandin-synthesis inhibitors and uterine relaxing activity. J Ethnopharmacol 1999; 64:9~14
26 Van Voorhis BJ, Huettner PC, Clark MR, et al. Immuno- histochemical localization of prostaglandin H synthase in the female reproductive tract and endometriosis. Am J Obstet Gynecol 1990; 163(l Pt l):57~62
27 Sheng H,Shao J,Washington M K,et al.Prostaglandin.E2 increases growt h and motility of colorectal carcinoma cells[J].J Biol Chem,2001,276(21):18075~18081
28 Dermott J M Reddy MR, Onesime D, et al.Oncogenic mutant of Galphal 2 stimulates cell proliferation t hrough cyclooxygenase-2 signaling pathway [J]. Oncogene, 1999, 18 (51):7185~7189
29 Cao Y, Pearman A T, Zimmerman GA, et al,Intracellar unesterified arachidonic acid signals apotosis[J].Proc Natl Acad Sci USA,2000,97(21):11280~11285
30 Tsujii M,DuBosi RN.Alterations in celluar adhesion and apotosis in epithelial cells overexpressing prostaglandinendoperoxide synthase 2[J].Cell,1995,83(3):221~226
31 Vivian Y. Shinl. William K.K. et a1. Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2. Carcinogenesis 2004 25(12):2487~2495
32 Tsujii M, KawanoS, Tsuji S, et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. 1998; 93: 705~ 716
33 Majima M, Isono M, Zkeda Y,et al.Significant roles of inducible cyclooxygenase(COX)-2 in angiogenesis in rat sponge implants[J]. Jpn J Pharmacol, 1997, 75:105~114
34 Liu XH,Kirschenbaum A,Yao S,et al.Upregulation of vascular endothelial growth factor by cobalt chloride- simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line[J].Clin Exp Metastasis,1999,17:687~694
35 Williams CS. Host Cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 2000; 105:1589~1594
36 Pichiule P, Chavez JC, Lamanna JC. Hypoxic regulation of angiopoientin-2 expression in endothelial cells. J Biol Chem 2004; 279:12171~12180
37 Yong W, Mahboubi K Haider A, et al. Cyclooxygenase-2 is required for tumor factor-α and angiotensinII-mediated proliferation of vascular smooth muscle cell. Circ Res 1989;86: 906~914
38 Prescott SM. Is cyclooxygenase-2 the alpha and the omegain cancer J Clin Invest 2000; 105:1511~1513
39 Koolwijk P, Kapiteijn K, Molenaar B, et al. Enhanced angiogenic capacity and urokinase-type plasnminogen activator expression by endothelial cells isolated from human endometrium. J Clin Endocrinol Metab, 2001, 86(7); 3359~3367
2 Pairet M.,and Engelhardt G.Distinct isoforms (COX-1 and COX-2) of cyclooxygenase: possible physiological and therapeutic implications. Fundam. Clin. Pharmacol.,1996,10:1~17
3 HlaT., Neilson K.Human cyclooxygenase-2 cDNA. Proc. Nat. Acad. Sci.,1992,89:7384~7388
4 Moran EM. Epidemiological and clinical aspects of nonsteroidal antiinflammatory drugs and cancer risks.J Environ Pathol Toxicol oncol,2002,21(2):193~201
5 Willimas CS , Dubois RN.Prostaglandins endoperoxide synthase; why two isoforms.Am J physiol,1996,270(3ptl): G393~400
6 Morita I,Schindler M,Regier MK,et al. Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2. J Biol Chem.,1995,270: 10902~10908
7 Lindsey K, Jager AK, Raidoo DM, et al.Screening of plants used by Southern African traditional healers in the treatment of dysmenorrhoea for prostaglandin-synthesis inhibitors and uterine relaxing activity. J Ethnopharmacol 1999; 64:9~14
8 Van Voorhis BJ, Huettner PC, Clark MR, et al. Immuno- histochemical localization of prostaglandin H synthase in the female reproductive tract and endometriosis. Am J Obstet Gynecol 1990; 163(l Pt l):57~62
9 Tsujli M,Kwanao S,Tsui S,et,al. Cyclooxygenase regulates angiogenesis,indueed by coloncancer cells. Cell,1998,93:705~716
10 Sheng H,Shao J,Momrw JD,et,al. Modulation of apoptosis and bcl-2 experssion by prostaglnadin E2 in human coloncancer cells. Cancer Res,1998,58:326~666
11 OtaH,Igarashi S,Saskai M,et,al. Disrtibution of cyelooxygenase-2 in eutopic and ectopic endomertium in endomertiosis and adenomyosis[J].Hum Repord,2001,6(3): 561~566
12 辛志敏,谢青贞,曹路敏,等。CuIUD 对妇女子宫内膜环氧化酶表达的影响。生殖与避孕,2005,25:28~32
13 Mann M, Sheng H J, et al.Targeting cyclooxyenase-2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology, 2001, 120:1713~1719
14 Majima M, Isono M, Zkeda Y,et al.Significant roles of inducible cyclooxygenase(COX)-2 in angiogenesis in rat sponge implants[J].Jpn J Pharmacol,1997,75:105~114
15 Liu XH, Kirschenbaum A, Yao S,et al.Upregulation of vascular endothelial growth factor by cobalt chloride-simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line[J].Clin Exp Metastasis, 1999, 17: 687~694
16 Chamoek-Jones DS,Shakrey AM,Rajput-williams J,et al. Identification and location of alternately spliced mRNAs for vascular endothelial growth factor in human uteurs and estrogen regulation in endometrial carcinoma cell lines. Biol Reprod,1993,48:1120~1128
17 Shifren JL,Tseng JF,Zaloudek CJ,et al. Ovarian steroid regulation of vaseular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstural cycle and in the pathogenesis of endothmetriosis. J Clin endocrinol Metab , 1996 , 81: 3112~3117
18 Sugino N,Kashida S,Karube-Harada A,etal. Expression of vascular endothelial growth factor (VEGF) and its receptors in human endometrium throughout the menstural cycle and in early pregnaney. Reproduction,2002,23,379~387
19 Hunag JC,liuDY,Dawood MY. The expression of vaseular Endothelial growth factor isoforms in cultured human endometrium stromal cells and its regulation by 17β- oestraliol [J]. Mol Hum Reprod,1998,4(6): 603~607
20 Greb RR,Heikinheimo O,Willimas RF,et al.Vaseular endothelial growth factor in primate endometrium is regulated by oestrogen-receptor and progesterone-receptor
1igands in vivo [J]. Hum Reprod,1997,12 (6): 1280~1292
21 Shakrey AM,Day K,Mc Pherson A,et al.Vaseular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endoerino lMetab,2000,85: 402~409
22 KawanoY,Matsui N,Kamihigashi S,et al. Eeffets of interfer- ongamma on secretion of vaseular endothelial growth factor by endometrial stromal cells. Am J Reprod Immunol,2000,43(1):47~52
23 Morry DS,Holt VJ,Keenan JA,et al. Vaseular endohtelial growth factor expression in cycling human endometrium. Fertil Steril,1996Jul; 66l:72~80
24 Naresh B,Sengupta J,BhagarvaV, et al. Immuno- histological localisation of vascular endothelial growth factor in human endometrium. Indian J Physiol Phamacol,1999APr; 43(2):165~170
25 Moller B,Rasmussen C,Lindblom B,et al. Expression of the angiogenic growth factors VEGF, FGF-2,EGF and their receptors in normal human endometrium during themenstural cycle. Mol Hum Reprod,2001Jan; 7(l): 65~72
26 Li XF ,Gregory J,Ahmed A.Immunolocalisation of vascularendothelial growth factor in human endometrium.Growth factors,1994;11(4):277~82
27 Bussolino F , Matflorani A , Persico G. Molecular mechanisms of blood vessel formation[J].TIBS,1997,22 (7):251~25
28 Johnanisson E. Eeffets on the endometrium,and exocervix following the use of local progestogen-releasing delivery systems. Contraception,1990 Oct:42(4):403~21
29 Lan TM , Affandi B , Rogers AP. The effects of levonogrestrel implants on vascular endothelial growth factor expression in the endometrium [J]. Mol Hum Repord,1999,5(1): 57~63
30 Toyoaki M,Jerffey R,Hurowitz BS,et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEBJ,1999,13: 9~22
31 Unemlri EM,Erikson ME,Roeceo SU,et al. Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vivo and is associated with menometrorrhagia in women [J]. Hum Reprod,1999,14(3):800~806
32 Hyder SM,Staneel GM,Chiappett Oa C,et al. Uterine expression of vaseular endothelial growth factor is inereased by estradiol and tamoxifen [J]. Cancer Res,1996,56(17): 3956~60
33 陈舟环.功能失调性子宫出血合并子宫肌瘤 43 例.广州医学,2002,33(1):36~37
34 Kawano Y,Nakamura S,Nasu K,et al.The effect of epidermal growth factor on vascular endothelial growth fator secretion by endometrial stromal cells[J].Clin Exp Med, 2002, 2(2):69~75
35 Ancelin M, Buteau-Lozano H, Meduri G, et al.A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF 189 regulates angiogenesis and vascular permeaility in human uterus [J].Proc Natl Acad Sci USA,2002,9(9):6023~6028
36 Mestre JR,Maekrell PJ,Rivadeneira DE. Redundancy in the signaling pathways and promoter elements regulating cyelooxygenase-2 gene expression in endotoxin-treated macrophage/monocytic cells. J Biol Chem.,2001: 276(6): 3977~82
37 Majima M, Isono M, Zkeda Y, et al.Significant roles of inducible cyclooxygenase (COX)-2 in angiogenesis in rat sponge implants [J]. Jpn J Pharmacol, 1997, 75: 105~114
38 Liu XH, Kirschenbaum A,Yao S, et al.Upregulation of vascular endothelial growth factor by cobalt chloride- simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line[J].Clin Exp Metastasis,1999,17:687~694
1 Folkman J.Seminars in medicine of the Beth Isarel Hospital, Boston.Clinical applications of research on angiogenesis.N Engl J Med 1995;333:1757~1763
2 Nakamura M, Abe Y and Tokunaga T. Pathological significance of vascular endothelial growth factor isoform expression in human cancer.Pathology international 2002; 2: 331~339
3 Ferrara N,Gerber HP, Le Couter J.The biology of VEGF and its receptors.Nat Med, 2003, 9(6): 669~676
4 Taylor RN,Lebovic DI,Hornung D.Endocrine and paracrine regulation of endometrial angiogenesis.Am NY Acad Sci,2001,943:109~121
5 Maas JW, Groothuis PG, Dunselman GA. Endometrial angiogenesis throughout the human menstrual cycle. Hum Reprod ,2001,16(8):1557~1561
6 Takahashi T, Shibuya M. the 230 kDa mature form of KDR/Flk-1(VEGF receptor-2)activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts.Oncogene 1997;14:2079~2089
7 Shirfen JL,Tseng JF,ferrara N.Ovarian steroid regulation of Vaseular endohtelial growth factor in human endometrium.J Clin Endometrinol Metab 1996; 81(8):3112~5
8 Barroso G,Barriouevo M,Rao P.Vaseular endohtelial growth factor,nitricoxde,andlept in follicular fluid levels correlatenegatively with embyro quality in IVF patients. Fert Ster,1999:72(6)
9 MollerB , LindblomB , Olovsson M.ExPerssion of the vascular Endothelial growth factors B and C and their receptors in Human endometrium during the menstrual cycle.Acta Obstet Gynecol Scand.2002Sep; 81(9):817~824
10 Gargett CE,Rogers PA. Human endometrial angiogenesis. Reproduction.2001 Feb; 121(2):181~186
11 Mueller MD, Lebovic DI, Garrett E,et al.Neutrophils infiltrating the endometrium express vascular endothelial growth factor :potential role in endothelial angiogenesis. Fertil Steril,2000,74(1):107~112
12 Kawano Y, Nakamura S,Nasu K,et al.The effect of epidermal growth factor on vascular endothelial growth factor secretion by endometrial stromal cells[J].Clin Exp Med,2002,2(2):69~75
13 Ancelin M, Buteau-Lozano H,Meduri G,et al.A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF 189 regulates angiogenesis and vascular permeaility in human uterus [J]. Proc Natl Acad Sci USA, 2002,9(9):6023~6028
14 Maynard SE, Min JY, Merchan J, et al. Excess placental solute fmslike tyrosine kinase 1 (sFlt-1) may contribute to endothelial dysfunction hypertension and proteinuria in preeclampsia. J Clin Invest, 2003, 111(5):649~658
15 Malik S,Day K,Perrault I,et al.Reduced levels of VEGF-Aand MMP-2 and MMP-9 activity and increased TNF in menstrual endometrium and efficient in women with menorrhagia.Hum Reprod,2006,25(3):896~901
16 Meduri G,Bausero P,Penot-Applanut M.Expression of vascular endothelial growth factor receptors in the human endometrium modulation during the menstrual cycle.Biol Reprod,2000,62(21):439~447
17 Pan JF, Yu YL,Wang Lj et al.The morphologic changes of endometrial spiral arterioales in IUD-induced menorrhagia. Adv Contracep,1994;10:213~222
18 沈铿,楼伟珍.环氧合酶和妇科肿瘤.沈铿,朗景和. 主编.人民卫生出版社.2002, 283~290
19 Hla T., Neilson K.Human cyclooxygenase-2 cDNA. Proc. Nat. Acad. Sci.,1992,89:7384~7388
20 Jones D.A.,Carlton D.P.,Mclntyre T.,et al. Molecular cloning of human prostaglandin endoperoxide synthase typeII and demonstration of expression in response to cytokines.J.Biol.Chem.,1993,268:9049~9054
21 Kraemer S.A.,Meade E.A.,Dewitt D.L. Prostaglandin endoperoxide synthase gene structure: identification of the transcriptional start site and 5-prime-flanking regulatory sequences.Arch.Biochem.BioPhys.,1992,293:391~400
22 Tazawa R., Xu X.-M.,Wu K.K.,et al.Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene.Biochem. Biophys. Res. Commun.,1994,203:190~199
23 Howe LR, Dannenberg AJ. A zole for cyclooxygenase-2 inhibitors in the prevention and treatment of cancer. Semin Oncol, 2002, 29:111~119
24 Morita I,Schindler M,Regier MK,et al. Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2. J Biol Chem.,1995,270:10902~10908
25 Lindsey K, Jager AK, Raidoo DM, et al.Screening of plants used by Southern African traditional healers in the treatment of dysmenorrhoea for prostaglandin-synthesis inhibitors and uterine relaxing activity. J Ethnopharmacol 1999; 64:9~14
26 Van Voorhis BJ, Huettner PC, Clark MR, et al. Immuno- histochemical localization of prostaglandin H synthase in the female reproductive tract and endometriosis. Am J Obstet Gynecol 1990; 163(l Pt l):57~62
27 Sheng H,Shao J,Washington M K,et al.Prostaglandin.E2 increases growt h and motility of colorectal carcinoma cells[J].J Biol Chem,2001,276(21):18075~18081
28 Dermott J M Reddy MR, Onesime D, et al.Oncogenic mutant of Galphal 2 stimulates cell proliferation t hrough cyclooxygenase-2 signaling pathway [J]. Oncogene, 1999, 18 (51):7185~7189
29 Cao Y, Pearman A T, Zimmerman GA, et al,Intracellar unesterified arachidonic acid signals apotosis[J].Proc Natl Acad Sci USA,2000,97(21):11280~11285
30 Tsujii M,DuBosi RN.Alterations in celluar adhesion and apotosis in epithelial cells overexpressing prostaglandinendoperoxide synthase 2[J].Cell,1995,83(3):221~226
31 Vivian Y. Shinl. William K.K. et a1. Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2. Carcinogenesis 2004 25(12):2487~2495
32 Tsujii M, KawanoS, Tsuji S, et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. 1998; 93: 705~ 716
33 Majima M, Isono M, Zkeda Y,et al.Significant roles of inducible cyclooxygenase(COX)-2 in angiogenesis in rat sponge implants[J]. Jpn J Pharmacol, 1997, 75:105~114
34 Liu XH,Kirschenbaum A,Yao S,et al.Upregulation of vascular endothelial growth factor by cobalt chloride- simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line[J].Clin Exp Metastasis,1999,17:687~694
35 Williams CS. Host Cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 2000; 105:1589~1594
36 Pichiule P, Chavez JC, Lamanna JC. Hypoxic regulation of angiopoientin-2 expression in endothelial cells. J Biol Chem 2004; 279:12171~12180
37 Yong W, Mahboubi K Haider A, et al. Cyclooxygenase-2 is required for tumor factor-α and angiotensinII-mediated proliferation of vascular smooth muscle cell. Circ Res 1989;86: 906~914
38 Prescott SM. Is cyclooxygenase-2 the alpha and the omegain cancer J Clin Invest 2000; 105:1511~1513
39 Koolwijk P, Kapiteijn K, Molenaar B, et al. Enhanced angiogenic capacity and urokinase-type plasnminogen activator expression by endothelial cells isolated from human endometrium. J Clin Endocrinol Metab, 2001, 86(7); 3359~3367