ДЕПРИВАЦИЯ VEGF ВЛИЯЕТ НА ЭКСПРЕССИЮ ЭНДОГЛИНА В КЛЕТКАХ ТРОФОБЛАСТА И ЕСТЕСТВЕННЫХ КИЛЛЕРАХ

Белки семейства VEGF участвуют в развитии многих клеточных популяций: эндотелиальных клеток, моноцитов и макрофагов, стволовых клеток, опухолевых клеток, мышечных клеток стенок сосудов, клеток трофобласта и в целом любых клеток, экспрессирующих рецепторы к VEGF. Нарушения, затрагивающие продукцию белков VEGF и проведение сигналов от них приводят ко многим патологическим состояниям, в том числе к аномалиям развития плаценты. Клетки трофобласта являются основной популяцией клеток, формирующей плаценту. Они вовлечены в процессы секреции и рецепции VEGF, фактора, необходимого для обеспечения ангиогенеза. Несмотря на это, на данный момент в литературе недостаточно данных о влиянии проведения сигналов от VEGF в клетках трофобласта на их функциональные особенности. Среди клеток окружения трофобласта, которые могут воздействовать на их активность в ходе беременности особой группой являются материнские иммунные клетки, в частности NK-клетки. Принимая во внимание высокую численность NK-клеток в децидуальной оболочке, необходимо учитывать их вклад в изменение фенотипа клеток трофобласта. В настоящем исследовании изучалась экспрессия NK-клетками и клетками трофобласта белков MICA и MICB, а также рецептора CD105. Молекулы MICA и MICB являются маркерами стресса и позволяют судить о жизнеспособности клеток. Рецептор CD105 экспрессирован на поверхности некоторых популяций клеток и участвует в передаче сигнала от белков семейства TGFβ. В частности, показано, что эндоглин регулирует сигналинг от TGFβ путем направления сигнала через пути SMAD2/3 или SMAD1/5/8. Эндоглин, согласно литературе, ингибирует сигналинг, задействующий белок SMAD3. Играет ли эндоглин ту же роль в случае NK-клеток и трофобласта неизвестно. Изучение изменений в экспрессии эндоглина является актуальной проблемой, поскольку сигналы от TGFβ необходимы при дифференцировке популяций трофобласта, а нарушения в механизмах сигналинга могут приводить к невынашиванию. В результате исследования мы показали, что VEGF играет роль в регуляции активности трофобласта и естественных киллеров. В частности, депривация VEGF-A моноклональными антителами против этого цитокина при сокультивировании трофобласта и NK-клеток приводит к угнетению экспрессии CD105 обеими популяциями клеток. При этом суточная инкубация трофобласта с антителами к VEGF не вызывала изменений в их устойчивости к цитотоксической активности естественных киллеров. Вместе полученные результаты говорят о том, что депривация VEGF приводит к значимым изменениям в рецепции белков семейства TGFβ клетками трофобласта и естественными киллерами.

1. Ander S.E., Diamond M.S.,Coyne C.B. Immune responses at the maternal-fetal interface. Sci Immunol, 2019, Vol.4, no 31. [10.1126/sciimmunol.aat6114] [https://www.ncbi.nlm.nih.gov/pubmed/30635356

2. https://immunology.sciencemag.org/content/immunology/4/31/eaat6114.full.pdf]

3. Apps R., Gardner L., Traherne J., Male V.,Moffett A. Natural-killer cell ligands at the maternal-fetal interface: UL-16 binding proteins, MHC class-I chain related molecules, HLA-F and CD48. Hum Reprod, 2008, Vol.23, no 11, pp. 2535-48. [10.1093/humrep/den223] [https://www.ncbi.nlm.nih.gov/pubmed/18658158]

4. Apte R.S., Chen D.S.,Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell, 2019, Vol.176, no 6, pp. 1248-1264. [10.1016/j.cell.2019.01.021] [https://www.ncbi.nlm.nih.gov/pubmed/30849371]

5. Cabrera-Sharp V., Read J.E., Richardson S., Kowalski A.A., Antczak D.F., Cartwright J.E., Mukherjee A.,de Mestre A.M. SMAD1/5 signaling in the early equine placenta regulates trophoblast differentiation and chorionic gonadotropin secretion. Endocrinology, 2014, Vol.155, no 8, pp. 3054-64. [10.1210/en.2013-2116] [https://www.ncbi.nlm.nih.gov/pubmed/24848867]

6. Chen D.B.,Zheng J. Regulation of placental angiogenesis. Microcirculation, 2014, Vol.21, no 1, pp. 15-25. [10.1111/micc.12093] [https://www.ncbi.nlm.nih.gov/pubmed/23981199]

7. Chen W.S., Kitson R.P.,Goldfarb R.H. Modulation of human NK cell lines by vascular endothelial growth factor and receptor VEGFR-1 (FLT-1). In Vivo, 2002, Vol.16, no 6, pp. 439-45. [https://www.ncbi.nlm.nih.gov/pubmed/12494887]

8. Clark D.E., Smith S.K., He Y., Day K.A., Licence D.R., Corps A.N., Lammoglia R.,Charnock-Jones D.S. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol Reprod, 1998, Vol.59, no 6, pp. 1540-8. [10.1095/biolreprod59.6.1540] [https://www.ncbi.nlm.nih.gov/pubmed/9828203

9. https://watermark.silverchair.com/biolreprod1540.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA6IwggOeBgkqhkiG9w0BBwagggOPMIIDiwIBADCCA4QGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMg7hZUSu19Vfp5F15AgEQgIIDVTeMpOl5VfmxO6HB6kEGUPF1K4FowNqLqtMpZZIqIM-uOr0XmQPaadW3xSTX07Lz4G0zvJeWRZ0nTX8kbTdzvcYGeg2Avb0L1ZJqQTWdL72PsNlt8eZ34saBJBFFzsIEFl6Eb6LzbC9B0gygrLaGK1_cVOR2HIro6FmDduNyK76dLUplgeSSW4CN1tDbnnzbPEYxmOEV3aXmUY-06V9PvRzDolQB7ejCVFIc0ygQUaxj7kj8qpKqaN6AiX7yBGWpod3gsDdFwoJ-2AwU8lG48fVW0x9G_RpSBmfqyebWMigTH8XTSo-hGtSxM0cn5u8HaplyOW_UhQuti9sLtVUDv-c_mzBnb2u4P_PxbZy5mP4FBaQKROC2lTd4qaiCkWg5qKENVDkGSHyeDZCWMHG61OBbuPgMA96INAy48JOga6dncw-hwmRHaVw7Ug6QqYqsD1pHYeP5hjnYjxqQ-J9ywjQNXk9QNv4nut_3X4jfhTvs_gUtO2bYZGz1IPeEiFYiyG4BCjhTeAyNz5Tqs1v9fAtuiLB06kf5X-hJHpgJJTscMlTKp-ZARcCFGStZrwM61Hf8L8vh6_cUrSP9AW0bF60n6l0RjJtyGVSKu6O9fdETtIWbv7F7ucHB6GScWqp9QuCYQ9uXVe3lR9en7G2NQ-Bnutf7KOdhhfu_DoQT9rRml5lPZVPcFWZNUgtLZEYKMMuKQ298JiL0EJtQnzp4wkwnt3gvl-GnxMnXbDyX8I1rr-DxpXpdNgjc93-x98tls5ZHqjf-9xbfNw3sdxmOSPiBSLLHTR3Iy9JLI2W9MPAy87GDBe5T__4jX9RW99TC4Oo6vxwCy8YLP3d6eZC5z8aGZef6pOjG9Ihuu5uL54ryYsbDfZqsPqGbfR8hTE6iH5aNRvemkaS3kCCzNmixcDRgNYyl2hwFneniO54A8oGMfHP4GW4EwljkdjM5j0WG1DuLBgBaHsKoXiKMwugrTyiJnrvHbnxS0FMddEQ1kylBhlYNMEhQ5WhP_TXRXG1H882KYcMHIc-ZPmZIcR94AQG0KU3aJ_UMSioWmtMiguBpoZEZYSAFXIxQKatbDRDV-OxQhosoB7y4sc6tfYDcHEQrgfS0eIZNl0l-SsQYk6GGImHya3c]

10. Clark D.E., Smith S.K., Licence D., Evans A.L.,Charnock-Jones D.S. Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation. J Endocrinol, 1998, Vol.159, no 3, pp. 459-67. [10.1677/joe.0.1590459] [https://www.ncbi.nlm.nih.gov/pubmed/9834463]

11. Eidukaite A., Siaurys A.,Tamosiunas V. Differential expression of KIR/NKAT2 and CD94 molecules on decidual and peripheral blood CD56bright and CD56dim natural killer cell subsets. Fertil Steril, 2004, Vol.81 Suppl 1, no, pp. 863-8. [10.1016/j.fertnstert.2003.10.019] [c]

12. Fitzpatrick T.E., Lash G.E., Yanaihara A., Charnock-Jones D.S., Macdonald-Goodfellow S.K.,Graham C.H. Inhibition of breast carcinoma and trophoblast cell invasiveness by vascular endothelial growth factor. Exp Cell Res, 2003, Vol.283, no 2, pp. 247-55. [10.1016/s0014-4827(02)00044-7] [https://www.ncbi.nlm.nih.gov/pubmed/12581744]

13. Fong G.H., Rossant J., Gertsenstein M.,Breitman M.L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature, 1995, Vol.376, no 6535, pp. 66-70. [10.1038/376066a0] [https://www.ncbi.nlm.nih.gov/pubmed/7596436

14. https://www.nature.com/articles/376066a0]

15. Garcia J., Hurwitz H.I., Sandler A.B., Miles D., Coleman R.L., Deurloo R.,Chinot O.L. Bevacizumab (Avastin(R)) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev, 2020, Vol.86, no, pp. 102017. [10.1016/j.ctrv.2020.102017] [https://www.ncbi.nlm.nih.gov/pubmed/32335505]

16. Gong J.H., Maki G.,Klingemann H.G. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia, 1994, Vol.8, no 4, pp. 652-8. [https://www.ncbi.nlm.nih.gov/pubmed/8152260]

17. Guo B., Slevin M., Li C., Parameshwar S., Liu D., Kumar P., Bernabeu C.,Kumar S. CD105 inhibits transforming growth factor-beta-Smad3 signalling. Anticancer Res, 2004, Vol.24, no 3a, pp. 1337-45. [https://www.ncbi.nlm.nih.gov/pubmed/15274293]

18. Haider S., Lackner A.I., Dietrich B., Kunihs V., Haslinger P., Meinhardt G., Maxian T., Saleh L., Fiala C., Pollheimer J., Latos P.A.,Knofler M. Transforming growth factor-beta signaling governs the differentiation program of extravillous trophoblasts in the developing human placenta. Proc Natl Acad Sci U S A, 2022, Vol.119, no 28, pp. e2120667119. [10.1073/pnas.2120667119] [https://www.ncbi.nlm.nih.gov/pubmed/35867736]

19. Hurwitz H.I., Fehrenbacher L., Hainsworth J.D., Heim W., Berlin J., Holmgren E., Hambleton J., Novotny W.F.,Kabbinavar F. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol, 2005, Vol.23, no 15, pp. 3502-8. [10.1200/JCO.2005.10.017] [https://www.ncbi.nlm.nih.gov/pubmed/15908660]

20. Ito N., Wernstedt C., Engstrom U.,Claesson-Welsh L. Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules. J Biol Chem, 1998, Vol.273, no 36, pp. 23410-8. [10.1074/jbc.273.36.23410] [https://www.ncbi.nlm.nih.gov/pubmed/9722576

21. https://www.sciencedirect.com/science/article/pii/S0021925819750042?via%3Dihub]

22. Jackson M.R., Carney E.W., Lye S.J.,Ritchie J.W. Localization of two angiogenic growth factors (PDECGF and VEGF) in human placentae throughout gestation. Placenta, 1994, Vol.15, no 4, pp. 341-53. [10.1016/0143-4004(94)90002-7] [https://www.ncbi.nlm.nih.gov/pubmed/7937592]

23. Jin X., Mao L., Zhao W., Liu L., Li Y., Li D., Zhang Y.,Du M. Decidualization-derived cAMP promotes decidual NK cells to be angiogenic phenotype. Am J Reprod Immunol, 2022, Vol.88, no 3, pp. e13540. [10.1111/aji.13540] [https://www.ncbi.nlm.nih.gov/pubmed/35348271]

24. Kendall R.L., Wang G.,Thomas K.A. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun, 1996, Vol.226, no 2, pp. 324-8. [10.1006/bbrc.1996.1355] [https://www.ncbi.nlm.nih.gov/pubmed/8806634

25. https://www.sciencedirect.com/science/article/pii/S0006291X96913558?via%3Dihub]

26. Kohler P.O.,Bridson W.E. Isolation of hormone-producing clonal lines of human choriocarcinoma. J Clin Endocrinol Metab, 1971, Vol.32, no 5, pp. 683-7. [10.1210/jcem-32-5-683] [https://www.ncbi.nlm.nih.gov/pubmed/5103722

27. https://academic.oup.com/jcem/article-abstract/32/5/683/2716353?redirectedFrom=fulltext

28. https://watermark.silverchair.com/jcem0683.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAp4wggKaBgkqhkiG9w0BBwagggKLMIIChwIBADCCAoAGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMhF502Mvc2Mu8FtegAgEQgIICUZnwT0t-HWZxwbzXnAz7SxyVCfcqp7SrRlusWKbGlOh09_ku3c612DJoxU_yGfapxlWd35ybR7iFmo6twZa1g3nk4dBu23q2fqDNI1aSlewAaeyjtvhQ7pb7HMMNruT5A1TJswCuHn09TrUXnHLg-2emkbumJ4hwIkF8xtK8QdBXE7RfhXaccxnorfVyJ7st6CbyV4cO6odbc_BXOq9KZqVtPjMGnB-BPjV6C3nTax3_Leb7_h4n65udEZ7l_2DuUiamhjlnWdax5sI3jtUW4cCdjySdtuE593OD_d-4UL0Fs4ijyVGJrQL8ZwxmRkD84AGxaeTKWzqECG4XSmQw84vpMEvBE4VpoeIAnb4hBBg3yChJCAh7QXDMOIUDkC8WIUJCyb0F5qycHhTepzf2gMv-fVjAZQbEvBXHd_VhwKAtwe9Ps44IUUnTZ8mkGuI6QB2yx1uqlxruBityIMvRjgNwg-wV5UjiqyMHHoViPynkSyF1GVgQIk77gvCso5-_mdFq7QM-xGau2rb4OZveiDYGDDDpLKQZgzRly6T3CH5V8RPGewjaiNMvPJnJ_QDZARbe1u8V0NQHG13xd1_mHR7-S9q91IIkiIR92lw4GTWSouOL2YK2WqA8f4-d5yi2LlIWfdpVzMFyeokMu9-JSEb1YN8mnCkx-TmDsCF7cZ9F7GBUtqgtuXe3gmpNMqPKbcDZI1JIxQWPYReNMRI4JNdPXR9g73DYGHIqaPLzqj5ozg0GjB7omgd6DFbOoKIQ1bTKUm8TSmA-nXXGecb_NH8W]

29. Laakkonen J.P., Lahteenvuo J., Jauhiainen S., Heikura T.,Yla-Herttuala S. Beyond endothelial cells: Vascular endothelial growth factors in heart, vascular anomalies and placenta. Vascul Pharmacol, 2019, Vol.112, no, pp. 91-101. [10.1016/j.vph.2018.10.005] [https://www.ncbi.nlm.nih.gov/pubmed/30342234

30. https://www.sciencedirect.com/science/article/pii/S1537189118301630?via%3Dihub]

31. Lebrin F., Goumans M.J., Jonker L., Carvalho R.L., Valdimarsdottir G., Thorikay M., Mummery C., Arthur H.M.,ten Dijke P. Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J, 2004, Vol.23, no 20, pp. 4018-28. [10.1038/sj.emboj.7600386] [https://www.ncbi.nlm.nih.gov/pubmed/15385967

32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC524335/pdf/7600386a.pdf]

33. Li D.Y., Sorensen L.K., Brooke B.S., Urness L.D., Davis E.C., Taylor D.G., Boak B.B.,Wendel D.P. Defective angiogenesis in mice lacking endoglin. Science, 1999, Vol.284, no 5419, pp. 1534-7. [10.1126/science.284.5419.1534] [https://www.ncbi.nlm.nih.gov/pubmed/10348742

34. https://science.sciencemag.org/content/284/5419/1534.long]

35. Li Y., Zhu H., Klausen C., Peng B.,Leung P.C. Vascular Endothelial Growth Factor-A (VEGF-A) Mediates Activin A-Induced Human Trophoblast Endothelial-Like Tube Formation. Endocrinology, 2015, Vol.156, no 11, pp. 4257-68. [10.1210/en.2015-1228] [https://www.ncbi.nlm.nih.gov/pubmed/26327470

36. https://watermark.silverchair.com/endo4257.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtowggLWBgkqhkiG9w0BBwagggLHMIICwwIBADCCArwGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpe2nuFQwuQewEslaAgEQgIICjdrQiDaVCl3BcxnvJU4NI6c1l-rtKi4UoKjE_ajx30U9EBbMh5UgSVwnadaLXB-GlLt0KGx4yuixaCDYW904MBVOAyLwq75Kb86x1ECbo9_Kok9RE5rQe2aVrk1sicKR5zAXxvnOfUT_7iPD2gKu38Y_9Od5ZSslcCkdQoOEk-oHxE8wzvAUxfNXUEsIS_mtxSJtURAwidM8UNfTzfqzCsds4cERJk7Wbq5rfTTsqUA9rJBMabNLFcQdaRv7wQZo-OhxUhBASOFY8iS2wfRwgZOztYjiap07YGTxzFDxqyEQOMVgxXZI0cfwYO_4h_u1owDGDOEI9ecIo9WTfTPKlH89oU84ed5oyK43khOZQjlnQZysPFjJkfwvSlR3cd5KAYxnQ8wXl1vA2vj3M7Eudh62v793HfNxJj8BIT1teEGmu8LqqLPILoTWj_m1ILaE5NJ4V1CRmi_BV6b325FbGdzRRYSqrDKiZiqfXZhlWq1AUoUmsTCssY56alTbA4IWiorewjiJFPlDg-Io1pJ71-R832m4tWBTCWplF_1ItW0YN5uWtQVjcwJGysC1K0bShxGU2wmZO1WVsVBuk5HxMGqmXWBe16tlXoPNDMA0vh4oVjfDzHb7Ig6ftctZ6HetrhM9o3q2nl_3Mq1oCT84v34uctb9IMH_HtKcw8THOzMVGf9NHJ9gNI63ke50M93uWp8r_XiKIMgLF4dWZMROJWhO3WVgXYydH1OLufTWBW1Y4v5ojSWVCTDtkgbZAwEzlgdoANRs2Qof5-YZBmrjPxG8xCBHKBn5JZ9J8YjHtFXV3WP2fpxw6yrtYANigdOq0q4rj7xrylVRd_QrfaYC_S-y1KOvlZeUuq3MymOL]

37. Maynard S.E., Min J.Y., Merchan J., Lim K.H., Li J., Mondal S., Libermann T.A., Morgan J.P., Sellke F.W., Stillman I.E., Epstein F.H., Sukhatme V.P.,Karumanchi S.A. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest, 2003, Vol.111, no 5, pp. 649-58. [10.1172/JCI17189] [https://www.ncbi.nlm.nih.gov/pubmed/12618519

38. https://dm5migu4zj3pb.cloudfront.net/manuscripts/17000/17189/JCI0317189.pdf]

39. Melder R.J., Koenig G.C., Witwer B.P., Safabakhsh N., Munn L.L.,Jain R.K. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med, 1996, Vol.2, no 9, pp. 992-7. [10.1038/nm0996-992] [https://www.ncbi.nlm.nih.gov/pubmed/8782456]

40. Melincovici C.S., Bosca A.B., Susman S., Marginean M., Mihu C., Istrate M., Moldovan I.M., Roman A.L.,Mihu C.M. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol, 2018, Vol.59, no 2, pp. 455-467. [https://www.ncbi.nlm.nih.gov/pubmed/30173249]

41. Mikhailova V., Khokhlova E., Grebenkina P., Salloum Z., Nikolaenkov I., Markova K., Davidova A., Selkov S.,Sokolov D. NK-92 cells change their phenotype and function when cocultured with IL-15, IL-18 and trophoblast cells. Immunobiology, 2021, Vol.226, no 5, pp. 152125. [10.1016/j.imbio.2021.152125] [https://www.ncbi.nlm.nih.gov/pubmed/34365089]

42. Naderan M., Sabzevary M., Rezaii K., Banafshehafshan A.,Hantoushzadeh S. Intravitreal anti-vascular endothelial growth factor medications during pregnancy: current perspective. Int Ophthalmol, 2021, Vol.41, no 2, pp. 743-751. [10.1007/s10792-020-01610-2] [https://www.ncbi.nlm.nih.gov/pubmed/33044671]

43. Nickel J., Ten Dijke P.,Mueller T.D. TGF-beta family co-receptor function and signaling. Acta Biochim Biophys Sin (Shanghai), 2018, Vol.50, no 1, pp. 12-36. [10.1093/abbs/gmx126] [https://www.ncbi.nlm.nih.gov/pubmed/29293886]

44. Papadopoulos N., Martin J., Ruan Q., Rafique A., Rosconi M.P., Shi E., Pyles E.A., Yancopoulos G.D., Stahl N.,Wiegand S.J. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis, 2012, Vol.15, no 2, pp. 171-85. [10.1007/s10456-011-9249-6] [https://www.ncbi.nlm.nih.gov/pubmed/22302382]

45. Rajagopalan S.,Long E.O. KIR2DL4 (CD158d): An activation receptor for HLA-G. Front Immunol, 2012, Vol.3, no, pp. 258. [10.3389/fimmu.2012.00258] [https://www.ncbi.nlm.nih.gov/pubmed/22934097

46. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422731/pdf/fimmu-03-00258.pdf]

47. Sandler A., Gray R., Perry M.C., Brahmer J., Schiller J.H., Dowlati A., Lilenbaum R.,Johnson D.H. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med, 2006, Vol.355, no 24, pp. 2542-50. [10.1056/NEJMoa061884] [https://www.ncbi.nlm.nih.gov/pubmed/17167137]

48. Scherner O., Meurer S.K., Tihaa L., Gressner A.M.,Weiskirchen R. Endoglin differentially modulates antagonistic transforming growth factor-beta1 and BMP-7 signaling. J Biol Chem, 2007, Vol.282, no 19, pp. 13934-43. [10.1074/jbc.M611062200] [https://www.ncbi.nlm.nih.gov/pubmed/17376778]

49. Schiessl B., Innes B.A., Bulmer J.N., Otun H.A., Chadwick T.J., Robson S.C.,Lash G.E. Localization of angiogenic growth factors and their receptors in the human placental bed throughout normal human pregnancy. Placenta, 2009, Vol.30, no 1, pp. 79-87. [10.1016/j.placenta.2008.10.004] [https://www.ncbi.nlm.nih.gov/pubmed/19010534]

50. Sharkey A.M., Charnock-Jones D.S., Boocock C.A., Brown K.D.,Smith S.K. Expression of mRNA for vascular endothelial growth factor in human placenta. J Reprod Fertil, 1993, Vol.99, no 2, pp. 609-15. [10.1530/jrf.0.0990609] [https://www.ncbi.nlm.nih.gov/pubmed/8107046]

51. Sharma S., Godbole G.,Modi D. Decidual Control of Trophoblast Invasion. Am J Reprod Immunol, 2016, Vol.75, no 3, pp. 341-50. [10.1111/aji.12466] [https://www.ncbi.nlm.nih.gov/pubmed/26755153

52. https://onlinelibrary.wiley.com/doi/full/10.1111/aji.12466

53. https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/aji.12466?download=true]

54. Simons M., Gordon E.,Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol, 2016, Vol.17, no 10, pp. 611-25. [10.1038/nrm.2016.87] [https://www.ncbi.nlm.nih.gov/pubmed/27461391

55. https://www.nature.com/articles/nrm.2016.87.pdf]

56. Tan H.X., Yang S.L., Li M.Q.,Wang H.Y. Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion. Cell Commun Signal, 2020, Vol.18, no 1, pp. 73. [10.1186/s12964-020-00579-w] [https://www.ncbi.nlm.nih.gov/pubmed/32398034

57. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218578/pdf/12964_2020_Article_579.pdf]

58. Trembath A.P.,Markiewicz M.A. More than Decoration: Roles for Natural Killer Group 2 Member D Ligand Expression by Immune Cells. Front Immunol, 2018, Vol.9, no, pp. 231. [10.3389/fimmu.2018.00231] [https://www.ncbi.nlm.nih.gov/pubmed/29483917]

59. Vinnars M.T., Bjork E., Nagaev I., Ottander U., Bremme K., Holmlund U., Sverremark-Ekstrom E.,Mincheva-Nilsson L. Enhanced Th1 and inflammatory mRNA responses upregulate NK cell cytotoxicity and NKG2D ligand expression in human pre-eclamptic placenta and target it for NK cell attack. Am J Reprod Immunol, 2018, Vol.80, no 1, pp. e12969. [10.1111/aji.12969] [https://www.ncbi.nlm.nih.gov/pubmed/29741244]

60. Wallace A.E., Fraser R.,Cartwright J.E. Extravillous trophoblast and decidual natural killer cells: a remodelling partnership. Hum Reprod Update, 2012, Vol.18, no 4, pp. 458-71. [10.1093/humupd/dms015] [https://www.ncbi.nlm.nih.gov/pubmed/22523109

61. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373213/pdf/dms015.pdf]

62. Waltenberger J., Claesson-Welsh L., Siegbahn A., Shibuya M.,Heldin C.H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem, 1994, Vol.269, no 43, pp. 26988-95. [https://www.ncbi.nlm.nih.gov/pubmed/7929439

63. https://www.sciencedirect.com/science/article/pii/S0021925818471165?via%3Dihub]

64. Wang J., Ding J., Zhang S., Chen X., Yan S., Zhang Y.,Yin T. Decreased USP2a Expression Inhibits Trophoblast Invasion and Associates With Recurrent Miscarriage. Front Immunol, 2021, Vol.12, no, pp. 717370. [10.3389/fimmu.2021.717370] [https://www.ncbi.nlm.nih.gov/pubmed/34489969]

65. Wang X.Q., Zhou W.J., Hou X.X., Fu Q.,Li D.J. Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface. Cell Mol Immunol, 2018, Vol.15, no 12, pp. 1038-1046. [10.1038/s41423-018-0019-x] [https://www.ncbi.nlm.nih.gov/pubmed/29588487

66. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269500/pdf/41423_2018_Article_19.pdf]

67. Wu D., Luo S., Wang Y., Zhuang L., Chen Y.,Peng C. Smads in human trophoblast cells: expression, regulation and role in TGF-beta-induced transcriptional activity. Mol Cell Endocrinol, 2001, Vol.175, no 1-2, pp. 111-21. [10.1016/s0303-7207(01)00397-5] [https://www.ncbi.nlm.nih.gov/pubmed/11325521]

68. Yang F., Zheng Q.,Jin L. Dynamic Function and Composition Changes of Immune Cells During Normal and Pathological Pregnancy at the Maternal-Fetal Interface. Front Immunol, 2019, Vol.10, no, pp. 2317. [10.3389/fimmu.2019.02317] [https://www.ncbi.nlm.nih.gov/pubmed/31681264

69. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813251/pdf/fimmu-10-02317.pdf]

70. Yi Y., Cheng J.C., Klausen C.,Leung P.C.K. TGF-beta1 inhibits human trophoblast cell invasion by upregulating cyclooxygenase-2. Placenta, 2018, Vol.68, no, pp. 44-51. [10.1016/j.placenta.2018.06.313] [https://www.ncbi.nlm.nih.gov/pubmed/30055669]

71. Zhao J., Schlosser H.A., Wang Z., Qin J., Li J., Popp F., Popp M.C., Alakus H., Chon S.H., Hansen H.P., Neiss W.F., Jauch K.W., Bruns C.J.,Zhao Y. Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer. Cancers (Basel), 2019, Vol.11, no 6. [10.3390/cancers11060874] [https://www.ncbi.nlm.nih.gov/pubmed/31234517]

72. Zhou Y., McMaster M., Woo K., Janatpour M., Perry J., Karpanen T., Alitalo K., Damsky C.,Fisher S.J. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol, 2002, Vol.160, no 4, pp. 1405-23. [10.1016/S0002-9440(10)62567-9] [https://www.ncbi.nlm.nih.gov/pubmed/11943725

73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277330/pdf/3098.pdf]