Angiopoietin-1 and angiopoietin-2 are altered in polycystic ovarian syndrome (PCOS) during controlled ovarian stimulation

Journal of Angiogenesis Research

Henry E Malter¹  Richard V Grazi¹  David B Seifer¹  Reshef Tal¹ 

[1] Genesis Fertility & Reproductive Medicine, Division of Reproductive Endocrinology and Infertility, Maimonides Medical Center, 1355 84th Street, Brooklyn, NY, USA

关键词: Controlled ovarian stimulation (COS);    Polycystic ovarian syndrome (PCOS);    Angiogenesis;    Angiopoietin-2;    Angiopoietin-1;   

Others  :  801440
DOI  :  10.1186/2045-824X-5-18

 received in 2013-09-08, accepted in 2013-10-21,  发布年份 2013

【 摘 要 】

Polycystic ovarian syndrome (PCOS) ovaries are characterized by increased angiogenesis and hypervascularity. While angiopoietin-1 (Ang-1) and its antagonist, angiopoietin-2 (Ang-2), are essential for ovarian function and angiogenesis, the levels of Ang-1 and Ang-2 in PCOS are unknown. This was a prospective cohort study of 14 PCOS women and 14 matched controls undergoing controlled ovarian stimulation (COS). Serum was collected on day 3, hCG and retrieval days. Follicular fluid (FF) was collected on retrieval day. Serum Ang-1 and Ang-2 levels were constant throughout COS, but serum Ang-1 levels were increased at all time points in PCOS women compared with controls (p < 0.05). No differences between groups were found in serum Ang-2 levels or FF Ang-1 levels. However, FF Ang-2 levels were increased almost 2-fold in PCOS women compared with controls (p < 0.01), and correlated positively with number of oocytes retrieved (r = 0.65, p < 0.0001). This study is the first to provide evidence of an alteration in the Ang-1/Ang-2 system in PCOS women. The biological role of Ang-2 in promoting capillary leakage, the increased Ang-2 FF level in PCOS, and its correlation with number of oocytes suggest that Ang-2 may play an important role in the increased risk of ovarian hyperstimulation in PCOS.

【 授权许可】

   
2013 Tal et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Padmanabhan V: Polycystic ovary syndrome–“A riddle wrapped in a mystery inside an enigma”. J Clin Endocrinol Metab 2009, 94(6):1883-1885.
• [2]Qiao J, Feng HL: Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Hum Reprod Update 2011, 17(1):17-33.
• [3]Fraser HM, Wulff C: Angiogenesis in the corpus luteum. Reprod Biol Endocrinol 2003, 1:88. BioMed Central Full Text
• [4]Hazzard TM, Christenson LK, Stouffer RL: Changes in expression of vascular endothelial growth factor and angiopoietin-1 and -2 in the macaque corpus luteum during the menstrual cycle. Mol Hum Reprod 2000, 6(11):993-998.
• [5]Wulff C, Wilson H, Largue P, Duncan WC, Armstrong DG, Fraser HM: Angiogenesis in the human corpus luteum: localization and changes in angiopoietins, tie-2, and vascular endothelial growth factor messenger ribonucleic acid. J Clin Endocrinol Metab 2000, 85(11):4302-4309.
• [6]Sugino N, Suzuki T, Sakata A, Miwa I, Asada H, Taketani T, Yamagata Y, Tamura H: Angiogenesis in the human corpus luteum: changes in expression of angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancy. J Clin Endocrinol Metab 2005, 90(11):6141-6148.
• [7]Geva E, Jaffe RB: Role of vascular endothelial growth factor in ovarian physiology and pathology. Fertil Steril 2000, 74(3):429-438.
• [8]Ferrara N, Frantz G, LeCouter J, Dillard-Telm L, Pham T, Draksharapu A, Giordano T, Peale F: Differential expression of the angiogenic factor genes vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF in normal and polycystic human ovaries. Am J Pathol 2003, 162(6):1881-1893.
• [9]Agrawal R, Sladkevicius P, Engmann L, Conway GS, Payne NN, Bekis J, Tan SL, Campbell S, Jacobs HS: Serum vascular endothelial growth factor concentrations and ovarian stromal blood flow are increased in women with polycystic ovaries. Hum Reprod 1998, 13(3):651-655.
• [10]Artini PG, Monti M, Matteucci C, Valentino V, Cristello F, Genazzani AR: Vascular endothelial growth factor and basic fibroblast growth factor in polycystic ovary syndrome during controlled ovarian hyperstimulation. Gynecol Endocrinol 2006, 22(8):465-470.
• [11]Amin AF, Abd el-Aal DE, Darwish AM, Meki AR: Evaluation of the impact of laparoscopic ovarian drilling on Doppler indices of ovarian stromal blood flow, serum vascular endothelial growth factor, and insulin-like growth factor-1 in women with polycystic ovary syndrome. Fertil Steril 2003, 79(4):938-941.
• [12]Artini PG, Ruggiero M, Parisen Toldin MR, Monteleone P, Monti M, Cela V, Genazzani AR: Vascular endothelial growth factor and its soluble receptor in patients with polycystic ovary syndrome undergoing IVF. Hum Fertil (Camb) 2009, 12(1):40-44.
• [13]Carmeliet P: Angiogenesis in health and disease. Nat Med 2003, 9(6):653-660.
• [14]Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD: Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 2000, 6(4):460-463.
• [15]Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, et al.: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997, 277(5322):55-60.
• [16]Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J: Vascular-specific growth factors and blood vessel formation. Nature 2000, 407(6801):242-248.
• [17]Xu F, Stouffer RL: Local delivery of angiopoietin-2 into the preovulatory follicle terminates the menstrual cycle in rhesus monkeys. Biol Reprod 2005, 72(6):1352-1358.
• [18]Hurliman AK, Speroff L, Stouffer RL, Patton PE, Lee A, Molskness TA: Changes in circulating levels and ratios of angiopoietins during pregnancy but not during the menstrual cycle and controlled ovarian stimulation. Fertil Steril 2010, 93(5):1493-1499.
• [19]Sova H, Morin-Papunen L, Puistola U, Karihtala P: Distinctively low levels of serum 8-hydroxydeoxyguanosine in women with polycystic ovary syndrome. Fertil Steril 2010, 94(7):2670-2673.
• [20]Tal R, Seifer DB, Shohat-Tal A, Grazi RV, Malter HE: Transforming growth factor-beta1 and its receptor soluble endoglin are altered in polycystic ovary syndrome during controlled ovarian stimulation. Fertil Steril 2013, 100(2):538-543.
• [21]Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004, 19(1):41-47.
• [22]Mofarrahi M, Hussain SN: Expression and functional roles of angiopoietin-2 in skeletal muscles. PLoS One 2011, 6(7):e22882.
• [23]Xu Y, Yu Q: Angiopoietin-1, unlike angiopoietin-2, is incorporated into the extracellular matrix via its linker peptide region. J Biol Chem 2001, 276(37):34990-34998.
• [24]Procopio WN, Pelavin PI, Lee WM, Yeilding NM: Angiopoietin-1 and -2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity. J Biol Chem 1999, 274(42):30196-30201.
• [25]Pau E, Alonso-Muriel I, Gomez R, Novella E, Ruiz A, Garcia-Velasco JA, Simon C, Pellicer A: Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome. Hum Reprod 2006, 21(6):1453-1460.
• [26]Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, Simon C: The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1beta, interleukin-6, and vascular endothelial growth factor. Fertil Steril 1999, 71(3):482-489.
• [27]Neulen J, Wenzel D, Hornig C, Wunsch E, Weissenborn U, Grunwald K, Buttner R, Weich H: Poor responder-high responder: the importance of soluble vascular endothelial growth factor receptor 1 in ovarian stimulation protocols. Hum Reprod 2001, 16(4):621-626.
• [28]McClure N, Healy DL, Rogers PA, Sullivan J, Beaton L, Haning RV Jr, Connolly DT, Robertson DM: Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet 1994, 344(8917):235-236.
• [29]Soares SR, Gomez R, Simon C, Garcia-Velasco JA, Pellicer A: Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome. Hum Reprod Update 2008, 14(4):321-333.
• [30]Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, Sato TN, Yancopoulos GD: Increased vascularization in mice overexpressing angiopoietin-1. Science 1998, 282(5388):468-471.
• [31]Nourhaghighi N, Teichert-Kuliszewska K, Davis J, Stewart DJ, Nag S: Altered expression of angiopoietins during blood–brain barrier breakdown and angiogenesis. Lab Invest 2003, 83(8):1211-1222.
• [32]Roviezzo F, Tsigkos S, Kotanidou A, Bucci M, Brancaleone V, Cirino G, Papapetropoulos A: Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther 2005, 314(2):738-744.