Особенности гемодинамики матки у пациенток с полиморфизмом гена ММР2

Филипенкова Т.Е., Щербакова Л.Н., Балацкий А.В., Самоходская Л.М., Панина О.Б. Особенности гемодинамики матки у пациенток с полиморфизмом гена ММР2. Гинекология. 2021; 23 (5): 413–420.
DOI: 10.26442/20795696.2021.5.201056

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Filipenkova ТЕ, Shcherbakova LN, Balatskiy AV, Samokhodskaya LM, Panina OB. Uterine perfusion in patients with MMP2 gene polymorphisms. Gynecology. 2021; 23 (5): 413–420. DOI: 10.26442/20795696.2021.5.201056

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Аннотация

Цель. Изучить влияние аллельного полиморфизма гена ММР2 на перфузию матки у пациенток, планирующих беременность.
Материалы и методы. Обследовали 95 женщин, планирующих беременность. Проведены клинико-лабораторное обследование, анализ однонуклеотидных полиморфизмов rs2285052(-955A/C) и rs243865(-1306C/T) гена MMP2, ультразвуковое исследование на 18–25-й день менструального цикла с оценкой пульсационного индекса кровотока сосудов матки и качественной оценкой перфузии эндометрия и субэндометриальной зоны. В зависимости от выявленного генотипа пациенток разделили на 3 группы: 1-я – носительницы гаплотипа rs2285052(A)rs243865(T), 2-я – с rs2285052(A)rs243865(С) и 3-я – контрольная группа с генотипом rs2285052(С/С)rs243865(С/С).
Результаты. Снижение перфузии в субэндометриальной зоне выявили у 40,6, 44,4, 19,4% пациенток в 1, 2 и 3-й группах соответственно; в эндометрии – у 68,8, 55,6 и 36,1% обследованных в этих же группах. Отсутствие визуализации спиральных артерий – у 28,1, 14,8 и 11,1% пациенток в 1, 2 и 3-й группах соответственно.
Не обнаружено статистических различий пульсационного индекса кровотока сосудов матки в зависимости от генотипа.
Заключение. У пациенток с носительством аллелей А rs2285052 и Т rs243865 гена ММР2 статистически значимо чаще выявлялись качественные нарушения кровотока на уровне мелких сосудов, выражавшиеся в обеднении сосудистого рисунка эндометрия и субэндометриальной зоны, что может приводить к отсутствию наступления беременности. Эти ассоциации сильнее выражены для полиморфизма rs2285052. Одновременное определение полиморфизмов rs2285052 и rs243865 не дает дополнительной информации по сравнению с определением только rs2285052.

Ключевые слова: однонуклеотидный аллельный полиморфизм, гаплотип, матриксная металлопротеиназа 2, допплерометрия, маточные артерии

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Aim. To investigate the effect of allelic polymorphisms of the MMP2 gene on uterine perfusion in patients planning pregnancy.
Materials and methods. 95 women planning pregnancy were examined. The patients underwent clinical and laboratory examination, analysis of single nucleotide polymorphisms rs2285052 and rs243865 of the MMP2 gene, ultrasound examination on days 18–25 of the menstrual cycle with an assessment of the pulsatility index of blood flow of the uterine vessels and a qualitative assessment of endometrial and subendometrial perfusion. Depending on the genotype, the patients were divided into 3 groups: first – with haplotype rs2285052(A)rs243865(T), second – with haplotype rs2285052(A)rs243865(С), and a third control group with rs2285052(С/С)rs243865(С/С) genotype.
Results. Decreased perfusion in the subendometrial zone was found in 40.6, 44.4 and 19.4% of patients in the 1, 2 and 3 groups, respectively; decreased perfusion of endometrium – in 68.8, 55.6 and 36.1% of patients in the 1, 2 and 3 groups, respectively. Spiral arteries were not visualized in 28.1, 14.8 and 11.1% of patients in the 1, 2 and 3 groups, respectively. No statistical differences were found in the pulsatility index of uterine blood flow depending on the genotype.
Conclusion. In patients with the A rs2285052 and T rs243865 alleles of the MMP2 gene poor vascular patterns of the endometrium and subendometrial zone of the uterus were statistically significantly more frequent, which can lead to infertility. These associations are more pronounced for the rs2285052 polymorphism. The simultaneous determination of the rs2285052 and rs243865 polymorphisms does not provide additional information compared to the definition of rs2285052 alone.

Keywords: single nucleotide polymorphism, haplotypes, matrix metalloproteinase 2, doppler ultrasonography, uterine artery

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Список литературы

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20. Mercé LT, Barco MJ, Bau S, Troyano J. Are endometrial parameters by three-dimensional ultrasound and power Doppler angiography related to in vitro fertilization/embryo transfer outcome? Fertil Steril. 2008;89(1):111-7.
21. Mansour GM, Hussein SH, Abd El Hady RM, et al. Uterine artery flow velocity waveform (FVW) type and subednometrial vascularity in recurrent pregnancy loss. J Matern Neonatal Med. 2020;33(4):527-32. DOI:10.1080/14767058.2018.1495190
22. Yang W, Wu Z, Yu M, et al. Characteristics of midluteal phase uterine artery hemodynamics in patients with recurrent pregnancy loss. J Obstet Gynaecol Res. 2019;45(7):1230-5. DOI:10.1111/jog.13944
23. Ivanovski M, Damcevski N, Radevska B, Doicev G. Assessment of uterine artery and arcuate artery blood flow by transvaginal color Doppler ultrasound on the day of human chorionic gonadotropin administration as predictors of pregnancy in an in vitro fertilization program. Akush Ginekol (Sofiia). 2012;51(2):55-60.
24. Hoozemans DA, Schats R, Lambalk NB, et al. Serial uterine artery Doppler velocity parameters and human uterine receptivity in IVF/ICSI cycles. Ultrasound Obstet Gynecol. 2008;31(4):432-8.
25. Isaksson R, Tiitinen A, Cacciatore B. Uterine artery impedance to blood flow on the day of embryo transfer does not predict obstetric outcome. Ultrasound Obstet Gynecol. 2000;15(6):527-30. DOI:10.1046/j.1469-0705.2000.00133.x
26. Cho YJ, Kim NH, Jeong KA, et al. Association Between MMP-2 and TIMP-2 Gene Polymorphisms and Advanced-Stage Endometriosis in Korean Women. Am J Reprod Immunol. 2013;69(1):73-84.
27. Palei AC, Sandrim VC, Amaral LM, et al. Effects of Matrix Metalloproteinase (MMP)-2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy. Basic Clin Pharmacol Toxicol. 2012;111(4):262-7.
28. Singh N, Hussain S, Sharma U, et al. The protective role of the −1306C>T functional polymorphism in matrix metalloproteinase-2 gene is associated with cervical cancer: implication of human papillomavirus infection. Tumor Biol. 2016;37(4):5295-303.
29. Yoshii N, Hamatani T, Inagaki N, et al. Successful implantation after reducing matrix metalloproteinase activity in the uterine cavity. Reprod Biol Endocrinol. 2013;11(1):37.
30. Inagaki N, Stern C, McBain J, et al. Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Hum Reprod. 2003;18(3):608-15. DOI:10.1093/humrep/deg139
31. Maia-Filho VO, Rocha AM, Ferreira FP, et al. Matrix Metalloproteinases 2 and 9 and E-Cadherin Expression in the Endometrium During the Implantation Window of Infertile Women Before In Vitro Fertilization Treatment. Reprod Sci. 2015;22(4):416-22.
32. Ramu D, Venkatesan V, Paul SFD, Koshy T. Genetic variation in matrix metalloproteinase MMP2 and MMP9 as a risk factor for idiopathic recurrent spontaneous abortions in an Indian population. J Assist Reprod Genet. 2017;34(7):945-9. DOI:10.1007/s10815-017-0939-x
33. Neto SDJ, Machado JS, Araujo Júnior E, et al. Longitudinal assessment of maternal-fetal Doppler parameters and maternal plasma level of matrix metalloproteinases 2 and 9. J Matern Neonatal Med. 2016;29(24):3967-70. DOI:10.3109/14767058.2016.1152247

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1. Sardana D, Upadhyay A, Deepika K, et al. Correlation of subendometrial-endometrial blood flow assessment by two-dimensional power Doppler with pregnancy outcome in frozen-thawed embryo transfer cycles. J Hum Reprod Sci. 2014;7(2):130.
2. Troskina E. Besplodie nejasnogo geneza. Znachenie vnutrimatochnoj perfuzii. Avtoref. dis. ... kand. med. nauk. Moscow, 2014 (in Russian).
3. Chien LW, Au HK, Chen PL, et al. Assessment of uterine receptivity by the endometrial-subendometrial blood flow distribution pattern in women undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2002;78(2):245-51. DOI:10.1016/s0015-0282(02)03223-5
4. Jokimaa V, Oksjoki S, Kujari H, et al. Altered expression of genes involved in the production and degradation of endometrial extracellular matrix in patients with unexplained infertility and recurrent miscarriages. Mol Hum Reprod. 2002;8(12):1111-6. DOI:10.1093/molehr/8.12.1111
5. O’Reilly MS, Wiederschain D, Stetler-Stevenson WG, et al. Regulation of Angiostatin Production by Matrix Metalloproteinase-2 in a Model of Concomitant Resistance. J Biol Chem. 1999;274(41):29568-71.
6. Fernandez-Patron C, Martinez-Cuesta MA, Salas E, et al. Differential regulation of platelet aggregation by matrix metalloproteinases-9 and -2. Thromb Haemost. 1999;82(6):1730-5.
7. Staun-Ram E, Goldman S, Gabarin D, Shalev E. Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion. Reprod Biol Endocrinol. 2004;2:59. DOI:10.1186/1477-7827-2-59
8. Salamonsen L. Role of proteases in implantation. Rev Reprod. 1999;4(1):11-22.
9. Price SJ, Greaves DR, Watkins H. Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene. Role of Sp1 in allele-specific transcriptional regulation. J Biol Chem. 2001;276(10):7549-58. DOI:10.1074/jbc.M010242200
10. Xu E, Xia X, Lü B, et al. Association of matrix metalloproteinase-2 and -9 promoter polymorphisms with colorectal cancer in Chinese. Mol Carcinog. 2007;46(11):924-9.
11. Filipenkova TE, Shcherbakova LN, Balatskii AV, et al. Polimorfizm genov, vliiaiushchikh na remodelirovanie soedinitel'noi tkani, u patsientok s besplodiem. Arkhiv akusherstva i ginekologii im. V.F. Snegireva. 2020;7(3):158-64 (in Russian). DOI:10.17816/2313-8726-2020-7-3-158-164
12. Li L, Liu J, Qin S, Li R. The association of polymorphisms in promoter region of MMP2 and MMP9 with recurrent spontaneous abortion risk in Chinese population. Medicine (Baltimore). 2018;97(40):e12561. DOI:10.1097/MD.0000000000012561
13. Borghese B, Chiche JD, Vernerey D, et al. Genetic polymorphisms of matrix metalloproteinase 12 and 13 genes are implicated in endometriosis progression. Hum Reprod. 2008;23(5):1207-13. DOI:10.1093/humrep/den007
14. Carlson CS, Eberle MA, Rieder MJ, et al. Selecting a Maximally Informative Set of Single-Nucleotide Polymorphisms for Association Analyses Using Linkage Disequilibrium. Am J Hum Genet. 2004;74(1):106-20.
15. Trifonova EA, Spiridonova MG, Gabidulina TV, et al. Analiz struktury neravnovesiia po stsepleniiu i assotsiatsii polimorfnykh variantov gena MTHFR s koronarnym aterosklerozom. Genetika. 2012;48(10):1207-20 (in Russian).
16. Lewontin RC. The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics. 1964;49(1):49-67.
17. Sole X, Guino E, Valls J, et al. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22(15):1928-9.
18. Kasius A, Smit JG, Torrance HL, et al. Endometrial thickness and pregnancy rates after IVF: A systematic review and meta-analysis. Hum Reprod Update. 2014;20(4):530-41. DOI:10.1093/humupd/dmu011
19. Richter KS, Bugge KR, Bromer JG, Levy MJ. Relationship between endometrial thickness and embryo implantation, based on 1,294 cycles of in vitro fertilization with transfer of two blastocyst-stage embryos. Fertil Steril. 2007;87(1):53-9.
20. Mercé LT, Barco MJ, Bau S, Troyano J. Are endometrial parameters by three-dimensional ultrasound and power Doppler angiography related to in vitro fertilization/embryo transfer outcome? Fertil Steril. 2008;89(1):111-7.
21. Mansour GM, Hussein SH, Abd El Hady RM, et al. Uterine artery flow velocity waveform (FVW) type and subednometrial vascularity in recurrent pregnancy loss. J Matern Neonatal Med. 2020;33(4):527-32. DOI:10.1080/14767058.2018.1495190
22. Yang W, Wu Z, Yu M, et al. Characteristics of midluteal phase uterine artery hemodynamics in patients with recurrent pregnancy loss. J Obstet Gynaecol Res. 2019;45(7):1230-5. DOI:10.1111/jog.13944
23. Ivanovski M, Damcevski N, Radevska B, Doicev G. Assessment of uterine artery and arcuate artery blood flow by transvaginal color Doppler ultrasound on the day of human chorionic gonadotropin administration as predictors of pregnancy in an in vitro fertilization program. Akush Ginekol (Sofiia). 2012;51(2):55-60.
24. Hoozemans DA, Schats R, Lambalk NB, et al. Serial uterine artery Doppler velocity parameters and human uterine receptivity in IVF/ICSI cycles. Ultrasound Obstet Gynecol. 2008;31(4):432-8.
25. Isaksson R, Tiitinen A, Cacciatore B. Uterine artery impedance to blood flow on the day of embryo transfer does not predict obstetric outcome. Ultrasound Obstet Gynecol. 2000;15(6):527-30. DOI:10.1046/j.1469-0705.2000.00133.x
26. Cho YJ, Kim NH, Jeong KA, et al. Association Between MMP-2 and TIMP-2 Gene Polymorphisms and Advanced-Stage Endometriosis in Korean Women. Am J Reprod Immunol. 2013;69(1):73-84.
27. Palei AC, Sandrim VC, Amaral LM, et al. Effects of Matrix Metalloproteinase (MMP)-2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy. Basic Clin Pharmacol Toxicol. 2012;111(4):262-7.
28. Singh N, Hussain S, Sharma U, et al. The protective role of the −1306C>T functional polymorphism in matrix metalloproteinase-2 gene is associated with cervical cancer: implication of human papillomavirus infection. Tumor Biol. 2016;37(4):5295-303.
29. Yoshii N, Hamatani T, Inagaki N, et al. Successful implantation after reducing matrix metalloproteinase activity in the uterine cavity. Reprod Biol Endocrinol. 2013;11(1):37.
30. Inagaki N, Stern C, McBain J, et al. Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Hum Reprod. 2003;18(3):608-15. DOI:10.1093/humrep/deg139
31. Maia-Filho VO, Rocha AM, Ferreira FP, et al. Matrix Metalloproteinases 2 and 9 and E-Cadherin Expression in the Endometrium During the Implantation Window of Infertile Women Before In Vitro Fertilization Treatment. Reprod Sci. 2015;22(4):416-22.
32. Ramu D, Venkatesan V, Paul SFD, Koshy T. Genetic variation in matrix metalloproteinase MMP2 and MMP9 as a risk factor for idiopathic recurrent spontaneous abortions in an Indian population. J Assist Reprod Genet. 2017;34(7):945-9. DOI:10.1007/s10815-017-0939-x
33. Neto SDJ, Machado JS, Araujo Júnior E, et al. Longitudinal assessment of maternal-fetal Doppler parameters and maternal plasma level of matrix metalloproteinases 2 and 9. J Matern Neonatal Med. 2016;29(24):3967-70. DOI:10.3109/14767058.2016.1152247

Авторы

Т.Е. Филипенкова*1, Л.Н. Щербакова1,2, А.В. Балацкий2,3, Л.М. Самоходская2, О.Б. Панина2

1 ГБУЗ «Центр планирования семьи и репродукции» Департамента здравоохранения г. Москвы, Москва, Россия;
2 ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова», Москва, Россия;
3 ФГБУ «Федеральный центра мозга и нейротехнологий» ФМБА России, Москва, Россия
*liya.fbm@gmail.com

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Tatiana E. Filipenkova*1, Liia N. Shcherbakova1,2, Aleksandr V. Balatskiy2,3, Larisa M. Samokhodskaya2, Olga B. Panina2

1 Family Planning and Reproduction Center, Moscow, Russia;
2 Lomonosov Moscow State University, Moscow, Russia;
3 Federal Center of Brain Research and Neurotechnologies, Moscow, Russia
*liya.fbm@gmail.com

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