Free Standard AU & NZ Shipping For All Book Orders Over $80!
Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Expression of vascular endothelial growth factor A isoforms is dysregulated in women with endometriosis

Kevin Danastas A C , Emily J. Miller B , Alison J. Hey-Cunningham B , Christopher R. Murphy A and Laura A. Lindsay A
+ Author Affiliations
- Author Affiliations

A Discipline of Anatomy and Histology, School of Medical Sciences and Bosch Institute, F13 Anderson Stuart Building, The University of Sydney, Sydney, NSW 2006, Australia.

B Department of Obstetrics, Gynaecology and Neonatology, K25 Medical Foundation Building, The University of Sydney, Sydney, NSW 2006, Australia.

C Corresponding author. Email: kdan6497@uni.sydney.edu.au

Reproduction, Fertility and Development 30(4) 651-657 https://doi.org/10.1071/RD17184
Submitted: 16 May 2017  Accepted: 12 September 2017   Published: 11 October 2017

Abstract

Angiogenesis is a critical step in the development of ectopic lesions during endometriosis. Although total vascular endothelial growth factor (VEGF) A is elevated in the peritoneal fluid of women with endometriosis, there are contradictory reports on how levels of total endometrial VEGFA are altered in this disease. Furthermore, limited research is available on different VEGFA isoforms in women with endometriosis. Thus, the aim of the present study was to analyse levels of various VEGFA isoforms in women with and without endometriosis at different stages of the menstrual cycle. Quantitative polymerase chain reaction analysis showed that total VEGFA was highest during menstruation in endometriosis compared with controls (P = 0.0373). VEGF121 and VEGF189 were similarly highest during menstruation in endometriosis compared with controls (P = 0.0165 and 0.0154 respectively). The present study is also the first to identify the natural expression of VEGF111 in human tissue, which is also highest during menstruation in endometriosis (P = 0.0464). This discovery of the natural production of VEGF111 in human endometrium, as well as the upregulation of VEGFA isoforms during menstruation in endometriosis, may shed further light on the development and progression of the disease, and improve our understanding of the regulation of endometrial angiogenesis.

Additional keywords: angiogenesis, endometrium, menstrual cycle, menstruation.


References

Banai, S., Shweiki, D., Pinson, A., Chandra, M., Lazarovici, G., and Keshet, E. (1994). Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis. Cardiovasc. Res. 28, 1176–1179.
Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXmslOqsrg%3D&md5=444e530a24132e07795d4ceb373534d3CAS |

Bourlev, V., Volkov, N., Pavlovitch, S., Lets, N., Larsson, A., and Ovsson, M. (2006). The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction 132, 501–509.
The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtFCgt7zO&md5=cea28b590a70f406e91d1602dc255e75CAS |

Buffet, N. C., Djakoure, C., Maitre, S. C., and Bouchard, P. (1998). Regulation of the human menstrual cycle. Front. Neuroendocrinol. 19, 151–186.
Regulation of the human menstrual cycle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXlt1aqtb0%3D&md5=921f66e55c4d6a3c1d00c1397542b4b7CAS |

Danastas, K., Combes, V., Lindsay, L. A., Grau, G. E., Thompson, M. B., and Murphy, C. R. (2015). VEGF111: new insights in tissue invasion. Front. Physiol. 6, 2.
VEGF111: new insights in tissue invasion.Crossref | GoogleScholarGoogle Scholar |

Delcombel, R., Janssen, L., Vassy, R., Gammons, M., Haddad, O., Richard, B., Letourneur, D., Bates, D., Hendricks, C., Waltenberger, J., Starzec, A., Sounni, N. E., Noel, A., Deroanne, C., Lambert, C., and Colige, A. (2013). New prospects in the roles of the C-terminal domains of VEGF-A and their cooperation for ligand binding, cellular signaling and vessels formation. Angiogenesis 16, 353–371.
New prospects in the roles of the C-terminal domains of VEGF-A and their cooperation for ligand binding, cellular signaling and vessels formation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXktF2rt7s%3D&md5=fb2a57570de93eb2eb8f2c0a7b4bc4caCAS |

Donnez, J., Smoes, P., Gillerot, S., Casanas-Roux, F., and Nisolle, M. (1998). Vascular endothelial growth factor (VEGF) in endometriosis. Hum. Reprod. 13, 1686–1690.
Vascular endothelial growth factor (VEGF) in endometriosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXkslOlu7w%3D&md5=1160446da240ce50aa8e77dfd7287d46CAS |

Garry, R., Hart, R., Karthigasu, K. A., and Burke, C. (2009). A re-appraisal of the morphological changes within the endometrium during menstruation: a hysteroscopic, histological and scanning electron microscopic study. Hum. Reprod. 24, 1393–1401.
A re-appraisal of the morphological changes within the endometrium during menstruation: a hysteroscopic, histological and scanning electron microscopic study.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD1MzltFyquw%3D%3D&md5=9919b18941ea0de181f38d36084f3904CAS |

Gashaw, I., Hastings, J. M., Jackson, K. S., Winterhager, E., and Fazleabas, A. T. (2006). Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria. Biol. Reprod. 74, 1060–1066.
Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XltVyrtrw%3D&md5=0aa731ce94e4d9d1db1af2e223c060fdCAS |

Gilabert-Estellés, J., Ramón, L. A., España, F., Gilabert, J., Vila, V., Réganon, E., Castelló, R., Chirivella, M., and Estellés, A. (2007). Expression of angiogenic factors in endometriosis: relationship to fibrinolytic and metalloproteinase systems. Hum. Reprod. 22, 2120–2127.
Expression of angiogenic factors in endometriosis: relationship to fibrinolytic and metalloproteinase systems.Crossref | GoogleScholarGoogle Scholar |

Giudice, L. C., and Kao, L. C. (2004). Endometriosis. Lancet 364, 1789–1799.
Endometriosis.Crossref | GoogleScholarGoogle Scholar |

Halme, J., Hammond, M. G., Hulka, J. F., Raj, S. G., and Talbert, L. M. (1984). Retrograde menstruation in healthy women and in patients with endometriosis. Obstet. Gynecol. 64, 151–154.
| 1:STN:280:DyaL2c3ks1GrtA%3D%3D&md5=3bd49a684609f05a08441922c9745e7aCAS |

Hastings, J. M., and Fazleabas, A. T. (2006). A baboon model for endometriosis: implications for fertility. Reprod. Biol. Endocrinol. 4, S7.
A baboon model for endometriosis: implications for fertility.Crossref | GoogleScholarGoogle Scholar |

Hey-Cunningham, A. J., Markham, R., Fraser, I. S., and Berbic, M. (2013). Dysregulation of vascular endothelial growth factors and their neuropilin receptors in the eutopic endometrium of women with endometriosis. Reprod. Sci. 20, 1382–1389.
Dysregulation of vascular endothelial growth factors and their neuropilin receptors in the eutopic endometrium of women with endometriosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhslWgtLrL&md5=2335c59cd255349e40d94cdd4f81b42cCAS |

Jones, A., Fujiyama, C., Blanche, C., Moore, J. W., Fuggle, S., Cranston, D., Bicknell, R., and Harris, A. L. (2001). Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1 alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines. Clin. Cancer Res. 7, 1263–1272.
| 1:CAS:528:DC%2BD3MXktlelsrw%3D&md5=75f81881ff4f2614687828cdeb8f7e66CAS |

Kyama, C. M., Overbergh, L., Mihalyi, A., Meuleman, C., Mwenda, J. M., Mathieu, C., and D’Hooghe, T. M. (2008). Endometrial and peritoneal expression of aromatase, cytokines, and adhesion factors in women with endometriosis. Fertil. Steril. 89, 301–310.
Endometrial and peritoneal expression of aromatase, cytokines, and adhesion factors in women with endometriosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXivFahuro%3D&md5=225e9440ba4681f8e81748aa549df0b4CAS |

Labied, S., Delforge, Y., Munaut, C., Blacher, S., Colige, A., Delcombel, R., Henry, L., Fransolet, M., Jouan, C., Perrier d’Hauterive, S., Noel, A., Nisolle, M., and Foidart, J. M. (2013). Isoform 111 of vascular endothelial growth factor (VEGF111) improves angiogenesis of ovarian tissue xenotransplantation. Transplantation 95, 426–433.
Isoform 111 of vascular endothelial growth factor (VEGF111) improves angiogenesis of ovarian tissue xenotransplantation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXit1aquro%3D&md5=df815a4bbcfac0ef51e3d210bf8ca7bfCAS |

Matsuzaki, S., Canis, M., Pouly, J. L., Dechelotte, P. J., and Mage, G. (2006). Analysis of aromatase and 17beta-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression in deep endometriosis and eutopic endometrium using laser capture microdissection. Fertil. Steril. 85, 308–313.
Analysis of aromatase and 17beta-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression in deep endometriosis and eutopic endometrium using laser capture microdissection.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xit12isrY%3D&md5=5982d9bcb1acec2d0952535e9d85c739CAS |

McLaren, J., Prentice, A., Charnock-Jones, D. S., and Smith, S. K. (1996). Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis. Hum. Reprod. 11, 220–223.
Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK28zisVCqsQ%3D%3D&md5=8ca4433208b18fca45970675ea270804CAS |

Mineur, P., Colige, A. C., Deroanne, C. F., Dubail, J., Kesteloot, F., Habraken, Y., Noel, A., Voo, S., Waltenberger, J., Lapiere, C. M., Nusgens, B. V., and Lambert, C. A. (2007). Newly identified biologically active and proteolysisresistant VEGF-A isoform VEGF111 is induced by genotoxic agents. J. Cell Biol. 179, 1261–1273.
Newly identified biologically active and proteolysisresistant VEGF-A isoform VEGF111 is induced by genotoxic agents.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhsVOgtL%2FP&md5=3682d0eddf8d0c9dabbc74b4155e4d31CAS |

Motta, C., Lupo, G., Rusciano, D., Olivieri, M., Lista, L., De Rosa, M., Pavone, V., and Anfuso, C. D. (2016). Molecular mechanisms mediating antiangiogenic action of the urokinase receptor-derived peptide UPARANT in human retinal endothelial cells. Invest. Ophthalmol. Vis. Sci. 57, 5723–5735.
Molecular mechanisms mediating antiangiogenic action of the urokinase receptor-derived peptide UPARANT in human retinal endothelial cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC28XitV2iu73M&md5=5d85277b760d145348dfb439f4cc868fCAS |

Mueller, M. D., Vigne, J. L., Minchenko, A., Lebovic, D. I., Leitman, D. C., and Taylor, R. N. (2000). Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc. Natl Acad. Sci. USA 97, 10972–10977.
Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXnt1ahsb0%3D&md5=c78f2d53a863f258dd3939e54c416b1dCAS |

Murphy, B. F., Belov, K., and Thompson, M. B. (2010). Evolution of viviparity and uterine angiogenesis: vascular endothelial growth factor (VEGF) in oviparous and viviparous skinks. J. Exp. Zool. B Mol. Dev. Evol. 314, 148–156.

Neutelings, T., Lambert, C. A., Nusgens, B. V., and Colige, A. C. (2013). Effects of mild cold shock (25 degrees C) followed by warming up at 37 degrees C on the cellular stress response. PLoS One 8, e69687.
Effects of mild cold shock (25 degrees C) followed by warming up at 37 degrees C on the cellular stress response.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXht1eju7bM&md5=52aba1a75014dd463f51d6ee1f6cb7dbCAS |

Noble, L. S., Simpson, E. R., Johns, A., and Bulun, S. E. (1996). Aromatase expression in endometriosis. J. Clin. Endocrinol. Metab. 81, 174–179.
| 1:CAS:528:DyaK28XkvVyktA%3D%3D&md5=65b5b6af7a47abb1545ba6db189d0583CAS |

Noyes, R. W., Hertig, A. T., and Rock, J. (1950). Dating the endometrial biopsy. Fertil. Steril. 1, 3–25.
Dating the endometrial biopsy.Crossref | GoogleScholarGoogle Scholar |

Osteen, K. G., Keller, N. R., Feltus, F. A., and Melner, M. H. (1999). Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium. Gynecol. Obstet. Invest. 48, 2–13.
Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXnsVemsL4%3D&md5=6528848ae5c19cac806c347aeeb81162CAS |

Redwine, D. B. (1987). Age-related evolution in color appearance of endometriosis. Fertil. Steril. 48, 1062–1063.
Age-related evolution in color appearance of endometriosis.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaL1c%2FlsFKhtw%3D%3D&md5=827e3f68ae80b73cb84740b96c300a78CAS |

Robinson, C. J., and Stringer, S. E. (2001). The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J. Cell Sci. 114, 853–865.
| 1:CAS:528:DC%2BD3MXit1eit7c%3D&md5=45543e3a08640e7a4da9caa9ba42a0efCAS |

Sampson, J. A. (1927a). Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am. J. Pathol. 3, 93–110.
| 1:STN:280:DC%2BC3critFaltA%3D%3D&md5=f4c69ec1be113deb9b67f41457da923dCAS |

Sampson, J. A. (1927b). Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am. J. Obstet. Gynecol. 14, 422–469.
Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity.Crossref | GoogleScholarGoogle Scholar |

Sharpe-Timms, K. L. (2001). Endometrial anomalies in women with endometriosis. Ann. N. Y. Acad. Sci. 943, 131–147.
Endometrial anomalies in women with endometriosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXnvVygurk%3D&md5=0b9aef49b524a9a06d34c4680e613caaCAS |

Shifren, J. L., Tseng, J. F., Zaloudek, C. J., Ryan, I. P., Meng, Y. G., Ferrara, N., Jaffe, R. B., and Taylor, R. N. (1996). Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J. Clin. Endocrinol. Metab. 81, 3112–3118.
| 1:CAS:528:DyaK28XkvFWqu7k%3D&md5=3846d7736a335840204942a32611c965CAS |

Takehara, M., Ueda, M., Yamashita, Y., Terai, Y., Hung, Y. C., and Ueki, M. (2004). Vascular endothelial growth factor A and C gene expression in endometriosis. Hum. Pathol. 35, 1369–1375.
Vascular endothelial growth factor A and C gene expression in endometriosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXhtVKltLrL&md5=e8ef7a83de9d6ef8c315a1f8c1f2fde1CAS |

Ueki, M. (1991). Histologic study of endometriosis and examination of lymphatic drainage in and from the uterus. Am. J. Obstet. Gynecol. 165, 201–209.
Histologic study of endometriosis and examination of lymphatic drainage in and from the uterus.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK3Mzgs12gtg%3D%3D&md5=79c00dd62da334b4a02943d507abf1a1CAS |

Wang, C., Hou, X., Mohapatra, S., Ma, Y., Cress, W. D., Pledger, W. J., and Chen, J. (2005). Activation of p27Kip1 Expression by E2F1. A negative feedback mechanism. J. Biol. Chem. 280, 12339–12343.
Activation of p27Kip1 Expression by E2F1. A negative feedback mechanism.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXislyht7c%3D&md5=3f8b9dc80ab8bbbf8672b270b934015aCAS |

Wellmann, S., Taube, T., Paal, K., von Einsiedel, M. G., Geilen, W., Seifert, G., Eckert, C., Henze, G., and Seeger, K. (2001). Specific reverse transcription-PCR quantification of vascular endothelial growth factor (VEGF) splice variants by LightCycler technology. Clin. Chem. 47, 654–660.
| 1:CAS:528:DC%2BD3MXis1Kjurk%3D&md5=58a48b1623fc3fc4fe3fddb38a8dc5c2CAS |

Wen, L., Chen, L. H., Li, H. Y., Chang, S. P., Liao, C. Y., Tsui, K. H., Sung, Y. J., and Chao, K. C. (2009). Roles of estrogen and progesterone in endometrial hemodynamics and vascular endothelial growth factor production. J. Chin. Med. Assoc. 72, 188–193.
Roles of estrogen and progesterone in endometrial hemodynamics and vascular endothelial growth factor production.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXmt1SntLk%3D&md5=bf7630040b80a263f8b4be03d07982d1CAS |

Whittington, C. M., Grau, G. E., Murphy, C. R., and Thompson, M. B. (2015). Unusual angiogenic factor plays a role in lizard pregnancy but is not unique to viviparity. J. Exp. Zool. B Mol. Dev. Evol. 324, 152–158.
Unusual angiogenic factor plays a role in lizard pregnancy but is not unique to viviparity.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXksFyltLc%3D&md5=4d8b816ae7f6cdcbbe939ff77c94312fCAS |

Whittington, C. M., Danastas, K., Grau, G. E., Murphy, C. R., and Thompson, M. B. (2017). Expression of VEGF 111 and other VEGF-A variants in the rat uterus is correlated with stage of pregnancy. J. Comp. Physiol. B 187, 353–360.
Expression of VEGF 111 and other VEGF-A variants in the rat uterus is correlated with stage of pregnancy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC28Xhs1GqsLnM&md5=554a37bfcaa68207b0ff7931f633516dCAS |

Xiong, Y., Liu, Y., Xiong, W. Q., Zhang, L., Liu, H. W., Du, Y., and Li, N. (2016). Hypoxia-inducible factor 1 alpha-induced epithelial–mesenchymal transition of endometrial epithelial cells may contribute to the development of endometriosis. Hum. Reprod. 31, 1327–1338.
Hypoxia-inducible factor 1 alpha-induced epithelial–mesenchymal transition of endometrial epithelial cells may contribute to the development of endometriosis.Crossref | GoogleScholarGoogle Scholar |

Yerlikaya, G., Balendran, S., Prostling, K., Reischer, T., Birner, P., Wenzl, R., Kuessel, L., Streubel, B., and Husslein, H. (2016). Comprehensive study of angiogenic factors in women with endometriosis compared to women without endometriosis. Eur. J. Obstet. Gynecol. Reprod. Biol. 204, 88–98.
Comprehensive study of angiogenic factors in women with endometriosis compared to women without endometriosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC28XhtlWnsrnL&md5=bf4401e32374f68d29ce8f76a5866622CAS |

Zeitoun, K. M., and Bulun, S. E. (1999). Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil. Steril. 72, 961–969.
Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3c%2FlvV2gtA%3D%3D&md5=0212df0d31abc805d022f74835eddd23CAS |