microRNA-203 Targets Insulin-Like Growth Factor Receptor 1 to Inhibit Trophoblast Vascular Remodeling to Augment Preeclampsia

Abstract

Objective Preeclampsia (PE) is a pregnancy-specific condition featured by high blood pressure, edema, and proteinuria. Research about the role of microRNA (miR)-203 in PE remains insufficient. This experiment is designed to investigate the specific role of miR-203 in trophoblasts in PE.

Study Design miR-203 expression in placenta tissues of normal pregnant women and PE patients was examined to analyze the relevance between miR-203 and PE diagnostic efficiency and between miR-203 and blood pressure (systolic pressure and diastolic pressure) and proteinuria of PE patients. miR-203 expression was downregulated in hypoxia-cultured trophoblasts using miR-203 inhibitor to assess matrix metalloproteinase-9 (MMP-9) level. Then, the angiogenesis of trophoblasts with different treatments was determined. Subsequently, the target relation between miR-203 and insulin-like growth factor receptor 1 (IGF-1R) was predicted and verified. Additionally, the effect of IGF-1R in the mechanism of miR-203 modulating trophoblast vascular remodeling was detected.

Results miR-203 was overexpressed in the placenta of PE patients and it acted as a promising diagnostic indicator for PE. Moreover, miR-203 was positively associated with blood pressure (systolic pressure and diastolic pressure) and proteinuria of PE patients. miR-203 silencing in hypoxia-cultured trophoblasts enhanced trophoblast vascular remodeling. Mechanically, miR-203 bound to IGF-1R to suppress its transcription. IGF-1R downregulation counteracted the promotive effect of miR-203 silencing on trophoblast vascular remodeling.

Conclusion miR-203 was overexpressed in PE, and it targeted IGF-1R to limit trophoblast vascular remodeling.

Key Points

• miR-203 is overexpressed in the placenta of PE patients.

• miR-203 acts as a potential diagnostic marker for PE.

• miR-203 targets IGF-1R to reduce trophoblast vascular remodeling in PE.

Keywords

microRNA-203 - IGF-1R - preeclampsia - trophoblast - vascular remodeling - posttranscriptional regulation

Ethical Approval

This study was approved and supervised by the ethics committee of Maternal and Child health Hospital of Hubei Province. All the patients signed the informed consent and they were informed with the object of this research. All procedures were strictly conducted in accordance with the code of ethics.

Authors' Contributions

All authors approved the final paper as submitted and agree to be accountable for all aspects of the work. L.Z. made substantial contributions to the conception of the present study. L.Z. and Y.L. performed the experiments and wrote the manuscript; Y.L. critically revised the paper.

Publication History

Received: 13 July 2021

Accepted: 24 October 2021

Article published online:
10 December 2021

• References

• 1 Paauw ND, Lely AT. Cardiovascular sequels during and after preeclampsia. Adv Exp Med Biol 2018; 1065: 455-470
• 2 Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res 2019; 124 (07) 1094-1112
• 3 Phipps E, Prasanna D, Brima W, Jim B. Preeclampsia: updates in pathogenesis, definitions, and guidelines. Clin J Am Soc Nephrol 2016; 11 (06) 1102-1113
• 4 Sircar M, Thadhani R, Karumanchi SA. Pathogenesis of preeclampsia. Curr Opin Nephrol Hypertens 2015; 24 (02) 131-138
• 5 Li Z, Zhou X, Gao W, Sun M, Chen H, Meng T. Circular RNA VRK1 facilitates pre-eclampsia progression via sponging miR-221-3P to regulate PTEN/Akt. J Cell Mol Med 2021
• 6 Cho S, Sohn YD, Kim S. et al. Reduced angiovasculogenic and increased inflammatory profiles of cord blood cells in severe but not mild preeclampsia. Sci Rep 2021; 11 (01) 3630
• 7 Bokslag A, van Weissenbruch M, Mol BW, de Groot CJ. Preeclampsia; short and long-term consequences for mother and neonate. Early Hum Dev 2016; 102: 47-50
• 8 Dymara-Konopka W, Laskowska M, Oleszczuk J. Preeclampsia - current management and future approach. Curr Pharm Biotechnol 2018; 19 (10) 786-796
• 9 Skalis G, Katsi V, Miliou A. et al. MicroRNAs in preeclampsia. MicroRNA 2019; 8 (01) 28-35
• 10 Yang S, Li H, Ge Q, Guo L, Chen F. Deregulated microRNA species in the plasma and placenta of patients with preeclampsia. Mol Med Rep 2015; 12 (01) 527-534
• 11 Li Z, Zhou G, Tao F, Cao Y, Han W, Li Q. circ-ZUFSP regulates trophoblasts migration and invasion through sponging miR-203 to regulate STOX1 expression. Biochem Biophys Res Commun 2020; 531 (04) 472-479
• 12 Wang LN, Yu WC, Du CH, Tong L, Cheng ZZ. Hypoxia is involved in hypoxic pulmonary hypertension through inhibiting the activation of FGF2 by miR-203. Eur Rev Med Pharmacol Sci 2018; 22 (24) 8866-8876
• 13 Liu F, Wu K, Wu W. et al. miR–203 contributes to pre–eclampsia via inhibition of VEGFA expression. Mol Med Rep 2018; 17 (04) 5627-5634
• 14 Gu Y, Zhu Z, Pei H. et al. Long non-coding RNA NNT-AS1 promotes cholangiocarcinoma cells proliferation and epithelial-to-mesenchymal transition through down-regulating miR-203. Aging (Albany NY) 2020; 12 (03) 2333-2346
• 15 Robajac D, Masnikosa R, Miković Ž, Mandić V, Nedić O. Oxidation of placental insulin and insulin-like growth factor receptors in mothers with diabetes mellitus or preeclampsia complicated with intrauterine growth restriction. Free Radic Res 2015; 49 (08) 984-989
• 16 Sun M, Ramchandran R, Chen J, Yang Q, Raj JU. Smooth muscle insulin-like growth factor-1 mediates hypoxia-induced pulmonary hypertension in neonatal mice. Am J Respir Cell Mol Biol 2016; 55 (06) 779-791
• 17 Sinkey RG, Battarbee AN, Bello NA, Ives CW, Oparil S, Tita ATN. Prevention, diagnosis, and management of hypertensive disorders of pregnancy: a comparison of international guidelines. Curr Hypertens Rep 2020; 22 (09) 66
• 18 Goradel NH, Mohammadi N, Haghi-Aminjan H, Farhood B, Negahdari B, Sahebkar A. Regulation of tumor angiogenesis by microRNAs: state of the art. J Cell Physiol 2019; 234 (02) 1099-1110
• 19 Yang Q, Gu WW, Gu Y. et al. Association of the peripheral blood levels of circulating microRNAs with both recurrent miscarriage and the outcomes of embryo transfer in an in vitro fertilization process. J Transl Med 2018; 16 (01) 186
• 20 Chen A, Yu R, Jiang S, Xia Y, Chen Y. Recent advances of MicroRNAs, long non-coding RNAs, and circular RNAs in preeclampsia. Front Physiol 2021; 12: 659638
• 21 Nikolov A, Popovski N. Role of gelatinases MMP-2 and MMP-9 in healthy and complicated pregnancy and their future potential as preeclampsia biomarkers. Diagnostics (Basel) 2021; 11 (03) 480
• 22 Díaz E, Cárdenas M, Ariza AC, Larrea F, Halhali A. Placental insulin and insulin-like growth factor I receptors in normal and preeclamptic pregnancies. Clin Biochem 2005; 38 (03) 243-247
• 23 Dhariwal NK, Lynde GC. Update in the management of patients with preeclampsia. Anesthesiol Clin 2017; 35 (01) 95-106
• 24 Sato Y. Endovascular trophoblast and spiral artery remodeling. Mol Cell Endocrinol 2020; 503: 110699
• 25 Hemmatzadeh M, Shomali N, Yousefzadeh Y, Mohammadi H, Ghasemzadeh A, Yousefi M. MicroRNAs: small molecules with a large impact on pre-eclampsia. J Cell Physiol 2020; 235 (04) 3235-3248
• 26 Wang Y, Dong Q, Gu Y, Groome LJ. Up-regulation of miR-203 expression induces endothelial inflammatory response: potential role in preeclampsia. Am J Reprod Immunol 2016; 76 (06) 482-490
• 27 Mayrink J, Souza RT, Feitosa FE. et al; Preterm SAMBA study group. Mean arterial blood pressure: potential predictive tool for preeclampsia in a cohort of healthy nulliparous pregnant women. BMC Pregnancy Childbirth 2019; 19 (01) 460
• 28 Özkara A, Kaya AE, Başbuğ A. et al. Proteinuria in preeclampsia: is it important?. Ginekol Pol 2018; 89 (05) 256-261
• 29 Albrecht ED, Pepe GJ. Regulation of uterine spiral artery remodeling: a review. Reprod Sci 2020; 27 (10) 1932-1942
• 30 Possomato-Vieira JS, Khalil RA. Mechanisms of endothelial dysfunction in hypertensive pregnancy and preeclampsia. Adv Pharmacol 2016; 77: 361-431
• 31 Panoutsopoulou K, Avgeris M, Mavridis K. et al. miR-203 is an independent molecular predictor of prognosis and treatment outcome in ovarian cancer: a multi-institutional study. Carcinogenesis 2020; 41 (04) 442-451
• 32 Hasanzadeh M, Movahedi M, Rejali M. et al. The potential prognostic and therapeutic application of tissue and circulating microRNAs in cervical cancer. J Cell Physiol 2019; 234 (02) 1289-1294
• 33 Wang X, Khalil RA. Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol 2018; 81: 241-330
• 34 Chen J, Khalil RA. Matrix metalloproteinases in normal pregnancy and preeclampsia. Prog Mol Biol Transl Sci 2017; 148: 87-165
• 35 Liu F, Wu W, Wu K. et al. MiR-203 participates in human placental angiogenesis by inhibiting VEGFA and VEGFR2 expression. Reprod Sci 2018; 25 (03) 358-365
• 36 Yu L, Wu S, Che S, Wu Y, Han N. Inhibitory role of miR-203 in the angiogenesis of mice with pathological retinal neovascularization disease through downregulation of SNAI2. Cell Signal 2020; 71: 109570
• 37 Mao Z, Fan L, Yu Q. et al. Abnormality of klotho signaling is involved in polycystic ovary syndrome. Reprod Sci 2018; 25 (03) 372-383
• 38 Geng Y, Sui C, Xun Y, Lai Q, Jin L. MiRNA-99a can regulate proliferation and apoptosis of human granulosa cells via targeting IGF-1R in polycystic ovary syndrome. J Assist Reprod Genet 2019; 36 (02) 211-221
• 39 Ma M, Zhou QJ, Xiong Y, Li B, Li XT. Preeclampsia is associated with hypermethylation of IGF-1 promoter mediated by DNMT1. Am J Transl Res 2018; 10 (01) 16-39
• 40 Yu M, Cui X, Wang H. et al. FUT8 drives the proliferation and invasion of trophoblastic cells via IGF-1/IGF-1R signaling pathway. Placenta 2019; 75: 45-53
• 41 Wu YT, Bi YM, Tan ZB. et al. Tanshinone I inhibits vascular smooth muscle cell proliferation by targeting insulin-like growth factor-1 receptor/phosphatidylinositol-3-kinase signaling pathway. Eur J Pharmacol 2019; 853: 93-102
• 42 Han JK, Kim HL, Jeon KH. et al. Peroxisome proliferator-activated receptor-δ activates endothelial progenitor cells to induce angio-myogenesis through matrix metallo-proteinase-9-mediated insulin-like growth factor-1 paracrine networks. Eur Heart J 2013; 34 (23) 1755-1765