The effects of certain angioneogenesis inhibitors in experimental endometriosis in rats

Home/2019, Vol. 7, No. 2/The effects of certain angioneogenesis inhibitors in experimental endometriosis in rats

Cell and Organ Transplantology. 2019; 7(2):140-147.
DOI: 10.22494/cot.v7i2.101

The effects of certain angioneogenesis inhibitors in experimental endometriosis in rats

Barbe A., Berbets A., Davydenko I., Yuzko V., Yuzko O.
Bukovinian State Medical University, Chernivtsi, Ukraine

Abstract
The pathogenetic theory of retrograde outflow of endometrial cells into the peritoneal cavity at endometriosis is gaining an increasing support. Adequate blood supply and angioneogenesis play an important role in successful implantation and occurrence of ectopic foci. VEGF plays an important role in this process. Determination of the pathways affecting the activity of this factor seems to be promising in terms of its effect produced on the early pathogenetic links of endometriosis.
Objectives: to determine the effectiveness of dopamine agonist cabergoline and highly selective COX-2 inhibitor celecoxib in an experimental model of external genital endometriosis in rats.
Methods. 83 outbred white female rats of Rattus Norvegicus Wistar were involved in the experiment. Experimental induction of endometriosis was performed by surgery and implantation of the autologous uterine fragments. The type and volume of experimental endometriosis lesions on the peritoneum of experimental animals were evaluated macroscopically as well as their hystologic examination were performed.
Results. Administration of a dopamine receptor agonist as a VEGF inhibitor separately was found to produce a pronounced inhibitory effect on ectopic endometrioid formation. However, the use of a dopamine receptor agonist in combination with a highly selective COX-2 inhibitor does not lead to potentiation or summation of their effects. At the same time, the use of COX-2 inhibitor alone has shown significantly lower efficacy than using the dopamine receptor agonist as a VEGF inhibitor.
Conclusion. At experimental endometriosis in rats, dopamine agonists and highly selective COX-2 inhibitors were found to be one of VEGF inhibitors available.

Key words: experimental endometriosis; angioneogenesis; VEGF; dopamine agonist; COX-2 inhibitor; cabergoline; celecoxib

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1. Guidice LC. Endometriosis. Lancet. 2010; 362:2389-98. https://doi.org/10.1016/S0140-6736(04)17403-5.
https://doi.org/10.1016/S0140-6736(04)17403-5
2. Brown J, Farquhar C. An overview of treatments for endometriosis. JAMA. 2015; 313(3):296-8. http://doi.org/10.1001/jama.2014.17119.
https://doi.org/10.1001/jama.2014.17119
PMid:25603001
3. Dunselman G, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014; 29:400-12. https://doi.org/10.1093/humrep/det457.
https://doi.org/10.1093/humrep/det457
PMid:24435778
4. Cheong YC, Smotra G, Williams AC. Non-surgical interventions for the management of chronic pelvic pain. Cochrane Database Systematic Review. 2014; 3. http://doi.org/10.1002/14651858.CD008797.pub2.
https://doi.org/10.1002/14651858.CD008797.pub2
PMid:24595586
5. Novella-Maestre E, Carda C, Noguera J, Ruiz-Sauri A, Garcia-Valsce JA. Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis. Hum Reprod. 2009; 24(5):1025-35. https://doi.org/10.1093/humrep/den499.
https://doi.org/10.1093/humrep/den499
PMid:19189995
6. Olivares C, Ricci A, Bilotas M, Baranao R, Meresman G. The inhibitory effect of celecoxib and rosiglitazone on expermimental endometriosis. Fertil Steril. 2011; 96(2):428-33. https://doi.org/10.1016/j.fertnstert.2011.05.063.
https://doi.org/10.1016/j.fertnstert.2011.05.063
PMid:21683949
7. Hashim HA. Potential role of aromatase inhibitors in the treatment of endometriosis. Int J Womens Health. 2014; 6:671-80. https://dx.doi.org/10.2147%2FIJWH.S34684.
https://doi.org/10.2147/IJWH.S34684
PMid:25092998 PMCid:PMC4113402
8. Macer ML, Taylor HS. Endometriosis and Infertility: A review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012; 39(4):535-49. https://doi.org/10.1016/j.ogc.2012.10.002.
https://doi.org/10.1016/j.ogc.2012.10.002
PMid:23182559 PMCid:PMC3538128
9. Laux-Biehlmann A, d’Hooghe T, Zollner T. Menstruation pulls the trigger for inflammation and pain in endometriosis. Trends Pharmacol Sci. 2015; 36(5):270-6. https://doi.org/10.1016/j.tips.2015.03.004.
https://doi.org/10.1016/j.tips.2015.03.004
PMid:25899467
10. Ranney B. Endometriosis: pathogenesis, sympyoms, and findings. Clin Obstet Gynecol.1988; 23(3):865-74.
https://doi.org/10.1097/00003081-198023030-00016
11. Donnwez J. Endometriosis: pathogenesis and pathophysiology. New Jersey: RW Shaw, 1990:120-128.
12. Lu Z, Zhang W, Jiang S, Zou J, Li Y. Effect of oxygen tensions on the proliferation and angiogenesis of endometriosis heterograft in severe combined immunodeficiency mice. Fertil Steril. 2014; 101(2):568-76. https://doi.org/10.1016/j.fertnstert.2013.10.039.
https://doi.org/10.1016/j.fertnstert.2013.10.039
PMid:24290003
13. Suzin J, Duechler M, Szuławska A, Czyż M, Kowalczyk-Amico K. Evaluation of selected angiogenic and inflammatory markers in endometriosis before and after danazol treatment. Reprod Fertil Dev. 2014; 26(3):414-20. https://doi.org/10.1071/RD12258.
https://doi.org/10.1071/RD12258
PMid:23544741
14. Folman J, Shing Y. Angiogenesis. J Biol Chem. 1992; 267(16):10931-4.
15. Machado D, Palumbo AJ, Santos J, Mattos R, dos Santos T, Seabra S, et al. A GFP endometriosis model reveals important morphological characteristics of the angiogenic process that govern benign and malignant diseases. Histol Histopathol. 2014; 29(7):903-12. https://doi.org/10.14670/HH-29.903.
16. Risau W. Mechanisms of angiogenesis. Nature. 1997; 386(6626):671-4.
https://doi.org/10.1038/386671a0
PMid:9109485
17. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002; 2(10):795-803.
https://doi.org/10.1038/nrc909
PMid:12360282
18. Nisolle M, Casanas-Roux F, Anaf V, Mine JM, Donnez J. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993; 59(3):681-4. https://doi.org/10.1016/S0015-0282(16)55823-3.
https://doi.org/10.1016/S0015-0282(16)55823-3
19. Shifren JL, Tseng JF, Zaloudek CJ. 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. 1996; 81(8):3112-8.
https://doi.org/10.1210/jcem.81.8.8768883
https://doi.org/10.1210/jc.81.8.3112
PMid:8768883
20. Hoeben A, Landuyt B, Highley MS, Wildiers H, van Oosterom AT, de Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004; 56(4):549-80. https://doi.org/10.1124/pr.56.4.3.
https://doi.org/10.1124/pr.56.4.3
PMid:15602010
21. Sharkey AM, Day K, McPherson A. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab. 2000; 85(1):402-9.
https://doi.org/10.1210/jc.85.1.402
https://doi.org/10.1210/jcem.85.1.6229
PMid:10634417
22. McLaren J, Prentice A, Charnock-Jones DS, Smith SK. Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis. Hum Reprod. 1996; 11(1):220-3.
https://doi.org/10.1093/oxfordjournals.humrep.a019023
PMid:8671190
23. Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M. Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod. 1998; 13(6):1686-90.
https://doi.org/10.1093/humrep/13.6.1686
PMid:9688413
24. McLaren J, Prentice A, Charnock-Jones DS. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest. 1996; 98(2):482-9.
https://doi.org/10.1172/JCI118815
PMid:8755660 PMCid:PMC507453
25. Bedaiwy MA, Dahoud W, Skomorovska-Prokvolit Y, Yi L, Liu JH, Falcone T, et al. Abundance and Localization of Progesterone Receptor Isoforms in Endometrium in Women With and Without Endometriosis and in Peritoneal and Ovarian Endometriotic Implants. Reprod Sci. 2015; 22(9):1153-61 https://doi.org/10.1177/1933719115585145.
https://doi.org/10.1177/1933719115585145
PMid:26037298 PMCid:PMC5933169
26. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989; 246:1306-9.
https://doi.org/10.1126/science.2479986
PMid:2479986
27. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J. Vascular permeability factor, an endothelial cell mitogen related to. Science. 1989; 246:1309-12.
https://doi.org/10.1126/science.2479987
PMid:2479987
28. Parick AA, Ellis LM. The vascular endothelial growth factor family and its receptors. Hematology/Oncology Clinics of North America. 2004; 18:951-71. https://doi.org/10.1016/j.hoc.2004.06.004.
https://doi.org/10.1016/j.hoc.2004.06.004
PMid:15474329
29. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endoc Rev. 2004; 25:581-611. https://doi.org/10.1210/er.2003-0027.
https://doi.org/10.1210/er.2003-0027
PMid:15294883
30. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996; 380:435-9.
https://doi.org/10.1038/380435a0
PMid:8602241
31. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996; 380:439-42.
https://doi.org/10.1038/380439a0
PMid:8602242
32. Pepper MS, Ferrara N, Orci L, Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 1992; 189:824-31.
https://doi.org/10.1016/0006-291X(92)92277-5
33. Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol. 2002; 29:10-4.
https://doi.org/10.1016/S0093-7754(02)70064-X
https://doi.org/10.1053/sonc.2002.37264
PMid:12516033
34. Cardones AR, Lionel LB. VEGF Inhibitors in Cancer Therapy. Curr Pharm Des. 2006; 12:387-94. https://doi.org/10.2174/138161206775201910.
https://doi.org/10.2174/138161206775201910
PMid:16454752
35. Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS. et al. Dopaminergic receptors linked to adenylate cyclase in human cerebromicrovascular endothelium. Nat Med. 2001; 7(5):569-74.
https://doi.org/10.1038/87895
PMid:11329058
36. Bacic F, Uemtsu S, McCarron RM, Spatz M. Dopaminergic receptors linked to adenylate cyclase in human cerebromicrovascular endothelium. J Neurochem. 1991; 57:1774-80.
https://doi.org/10.1111/j.1471-4159.1991.tb06380.x
PMid:1681036
37. Graybiel AM, Hirsch EC, Agid Y. The nigrostriatal system in Parkinson’s disease. Adv Neurol. 1990; 53:17-29.
38. Goldstein M, Deutch AY. Dopaminergic mechanisms in the pathogenesis of schizophrenia. FASEB. 1992; 6:2413-21.
https://doi.org/10.1096/fasebj.6.7.1348713
39. Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci. 1999; 22:123-44.
https://doi.org/10.1146/annurev.neuro.22.1.123
PMid:10202534
40. Egan MF, Weinberger DR. Neurobiology of schizophrenia. Curr Opin Neurobiol. 1997; 7:701-7.
https://doi.org/10.1016/S0959-4388(97)80092-X
41. Wick MM. 3,4-Dihydroxybenzylamine: a dopamine analog with enhanced antitumor activity against B16 melanoma. JNCI. 1979; 63:1465-7.
42. Wick MM. Levodopa and dopamine analogs: melanin precursors as antitumor agents in experimental human and murine leukemia. Cancer Treat Rep. 1979; 63:991-7.
43. Wick MM. Levodopa and dopamine analogs as DNA polymerase inhibitors and antitumor agents in human melanoma. Cancer Res. 1980; 40:1414-8.
44. Dasgupta PS, Lahiri T. Antitumor effect of i.p. dopamine in mice bearing Ehrlich ascites carcinoma. J Cancer Res Clin Oncol. 1987; 113:363-8.
https://doi.org/10.1007/BF00397720
PMid:3597522
45. Ricci A, Collier WL, Amenta F. Pharmacological characterization and autoradiographic localization of dopamine receptors in the portal vein. J Auton Pharmacol. 1994; 14:61-8.
https://doi.org/10.1111/j.1474-8673.1994.tb00590.x
PMid:8150810
46. Bacic F, Uematsu S, mcCarron RM, Spatz M. Dopaminergic receptors linked to adenylate cyclase in human cerebromicrovascular endothelium. J Neruchem. 1991; 57:1774-80.
https://doi.org/10.1111/j.1471-4159.1991.tb06380.x
PMid:1681036
47. Brown L. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. In: Goldberg I, Rosen E, editors. Regulation of Angiogenesis. Basel, Switzerland: Birkhauser; 1997.
48. Dvorak HF, Nagy JA, Feng D, Brown LF, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Cur Top Microbiol Immunol. 1999; 237:97-132.
https://doi.org/10.1007/978-3-642-59953-8_6
PMid:9893348
49. Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C. Pathophysiology and Immune Dysfunction in Endometriosis. BioMed Res Int. 2015; 2015:12. http://dx.doi.org/10.1155/2015/795976.
https://doi.org/10.1155/2015/795976
PMid:26247027 PMCid:PMC4515278
50. King C, Barbara C, Prentice A, Brenton J, Charnock-Jones D. Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma. J Pathol. 2015; 238(2):185-96. https://dx.doi.org/10.1002%2Fpath.4657.
https://doi.org/10.1002/path.4657
PMid:26456077 PMCid:PMC4855629
51. Ferrara N. Vascular endothelial growth factor: molecular and biological aspects. Cur Top Microbiol Immunol. 1999; 237:1-30.
https://doi.org/10.1016/S1569-2590(08)60162-7
https://doi.org/10.1007/978-3-642-59953-8_1
PMid:9893343
52. Turner HE. Angiogenesis in pituitary adenomas-relationship to endocrine function, treatment and outcome. J Endocrinol. 2000; 165:475-81.
https://doi.org/10.1677/joe.0.1650475
PMid:10810311
53. Nagai Y. Plasma levels of vascular endothelial growth factor in patients with acromegaly. Horm Metab Res. 2000; 32:326-9.
https://doi.org/10.1055/s-2007-978645
PMid:10983629
54. Berkman RA, Oldfield RH. Expression of vascular permeability factor / vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest. 1993; 91:153-9.
https://doi.org/10.1172/JCI116165
PMid:8380810 PMCid:PMC330009
55. Sahin M, Sahin E, Gumuslu S. Cyclooxygenase-2 in cancer and angiogenesis. Angiology. 2009; 60:242-53. https://doi.org/10.1177/0003319708318378.
https://doi.org/10.1177/0003319708318378
PMid:18505747
56. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007; 67:4507-13.
https://doi.org/10.1158/0008-5472.CAN-06-4174
PMid:17483367
57. Wu G, Luo J, Rana JS, Laham R, Sellke FW, Li J. Involvement of COX-2 in VEGF-induced angiogenesis via P38 and JNK pathways in vascular endothelial cells. Cardiovasc Res. 2006; 69:512-9. https://doi.org/10.1016/j.cardiores.2005.09.019.
https://doi.org/10.1016/j.cardiores.2005.09.019
PMid:16336951
58. Fukuda R, Kelly B, Semenza GI. Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. Cancer Res. 2003; 63:2330-4.
59. Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med. 2001; 7:569-74.
https://doi.org/10.1038/87895
PMid:11329058
60. Bhattacharya R, Sinha S, Yang SP, Patra C, Dutta S, Wang E. The neurotransmitter dopamine modulates vascular permeability in the endothelium. JMS. 2008; 3(14):112-8. https://dx.doi.org/10.1186%2F1750-2187-3-14.
https://doi.org/10.1186/1750-2187-3-14
PMid:18662404 PMCid:PMC2516513
61. Teunis MA, Kavelaars A, Voest E, Bakker JM, Ellenbroek BA, Cools AR. Reduced tumor growth, experimental metastasis formation, and angiogenesis in rats with a hyperreactive dopaminergic system. FASEB Journal. 2002; 16:1465-7.
https://doi.org/10.1096/fj.02-0145fje
PMid:12205050
62. Sinha S, Vohra PK, Bhattacharya R, Dutta S, Sinha S. Dopamine regulates phosphorylation of VEGF receptor 2 by engaging Src-homology-2-domain-containing protein tyrosine phosphatase 2. J Cell Sci. 2009; 122:3385-92. https://doi.org/10.1242/jcs.053124.
https://doi.org/10.1242/jcs.053124
PMid:19706677 PMCid:PMC2736867
63. Golan A, Winston RM, Dragenio R. Experimental endometriosis: a microsurgical animal model in rats. Isr J Med Sci. 1984; 20:1094-6. http://dx.doi.org/10.1590/S0102-86501997000400003.
https://doi.org/10.1590/S0102-86501997000400003
64. Hirata T, Osuga Y, Yoshino O, Hirota Y, Harada M, Takemura Y, et al. Development of an experimental model of endometriosis using mice that ubiquitously express green fluorescent protein. Hum Reprod. 2005; 20:2092-6. https://doi.org/10.1093/humrep/dei012.
https://doi.org/10.1093/humrep/dei012
PMid:15831509
65. Elgamal AD, Othman E-ER, Agmed FS. Ultrastructural Features of Eutopic Endometrium in a Rat Model of Endometriosis. JMAU. 2016; 4(1):20-7. https://doi.org/10.1016/j.jmau.2015.10.002.
https://doi.org/10.1016/j.jmau.2015.10.002
PMid:30023206 PMCid:PMC6014242
66. Rezende AC, Silva LA, Junior LJ, Gobbi H, Martins MM. Experimental model for endometriosis. Comparative histological study between the ectopic and eutopic endometrium. Acta Cir Bras. 1997; 12(4):226-30. http://dx.doi.org/10.1590/S0102-86501997000400003.
https://doi.org/10.1590/S0102-86501997000400003
67. Neto JN, Torres OJ, Coelho TM, Junior JN. Evaluation of the macroscopic growth degree of experimental endometriosis in rats. Acta Chir Brazil. 2007; 22(1):250-8. https://doi.org/10.1590/S0102-86502007000700003.
https://doi.org/10.1590/S0102-86502007000700003
PMid:17505648
68. Amaral VF, Lago EA, Kondo W, Guarita-Souza LC, Francisco JC. Development of an experimental model of endometriosis in rats. Rev Col Bras Cir. 2009; 36(3):120-5. https://doi.org/10.1093/humrep/dei012.
https://doi.org/10.1093/humrep/dei012
PMid:15831509
69. Xu L, Stevens J, Hilton MB, Seaman S, Conrads TP, Veenstra T, et al. COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models. Sci Transl Med. 2015; 6(242):1-12. http://doi.org/10.1126/scitranslmed.3008455.
https://doi.org/10.1126/scitranslmed.3008455
PMid:24964992 PMCid:PMC6309995

Barbe A, Berbets A, Davydenko I, Yuzko V, Yuzko O. The effects of certain angioneogenesis inhibitors in experimental endometriosis in rats. Cell and Organ Transplantology. 2019; 7(2):140-147. doi:10.22494/cot.v7i2.101

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