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Int J Med Sci 2021; 18(13):2814-2827. doi:10.7150/ijms.58992 This issue Cite

Research Paper

Abnormal proinflammatory and stressor environmental with increased the regulatory cellular IGF-1/PAPP-A/STC and Wnt-1/β-Catenin canonical pathway in placenta of women with Chronic venous Disease during Pregnancy

Miguel A Ortega^1,2,3,4✉, Oscar Fraile-Martínez¹, Miguel A Saez^1,5, Miguel A Álvarez-Mon^1,2, Ana M Gómez-Lahoz¹, Coral Bravo^2,6, Juan A De León Luis^7,8,9, Felipe Sainz^10,11, Santiago Coca^1,2,4, Ángel Asúnsolo^2,11, Jorge Monserrat^1,2, Luis G Guijarro^2,12*, Melchor Álvarez-Mon^1,2,4,13*, Julia Bujan^1,2,4*, Natalio García-Honduvilla^1,2,4*

1. Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain.
2. Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain.
3. Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias, 28806 Alcalá de Henares, Spain.
4. University Center for the Defense of Madrid (CUD-ACD), 28047 Madrid, Spain.
5. Pathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, 28801 Alcalá de Henares, Madrid, Spain.
6. Service of Gynecology and Obstetrics, Central University Hospital of Defense-UAH, Madrid, Spain.
7. Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain.
8. Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, Madrid 28009, Spain.
9. Health Research Institute Gregorio Marañón, 28009 Madrid, Spain.
10. Angiology and Vascular Surgery Unit, Central University Hospital of Defense-UAH, Madrid, Spain.
11. Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain.
12. Unit of Biochemistry and Molecular Biology (CIBEREHD), Department of System Biology, University of Alcalá, 28801 Alcalá de Henares, Spain.
13. Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine, University Hospital Príncipe de Asturias, (CIBEREHD), 28806 Alcalá de Henares, Spain.
* These authors shared senior authorship in this work.

✉ Corresponding author: miguel.angel.ortega92com; Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain

Abstract

Lower limbs venous insufficiency refers to a wide variety of venous disorders grouped by the term of chronic venous disease (CVD). Hemodynamic and hormonal changes related to pregnancy period, may promote the development of CVD affecting approximately 1 in 3 women. It has been shown that the presence of this condition is associated with damage and placental suffering. Thus, taking IGF-1/PAPP-A/STC-2, inflammatory cytokines production, PI3K/Akt and Wnt/ β-catenin pathways as a part of the alterations that occurs in the placenta due to CVD, the aim of this study will be to examine the main components of these pathways. Genic and protein expression of PAPP-A, STC-2, IGF-1, IRS-4 Wnt-1, β-catenin, c-myc, Cyclin D1, IL-4/IL-6 and PI3K/Akt/mTOR pathway will be analysed through RT-qPCR and immunohistochemical techniques in women with CVD (n=62) and pregnant women without this condition (HC) (n=52). PAPP-A, IGF-1, IL-4, IL-6, IRS-4, PI3K, Akt, mTOR, Wnt-1, β-catenin, c-myc and Cyclin D1 expression were found to be increased in women with CVD, whereas STC-2 were decreased in this group, compared to non-affected women. Our study has demonstrated that IGF-1/PAPP-A/STC-2 axis, PI3K/Akt and Wnt/β-catenin pathways, along with c-myc, Cyclin D1 and inflammatory cytokines are altered in placenta women with CVD. These results extent the knowledge that CVD is associated to a placenta damage with abnormal tissue environment and cellular regulation.

Keywords: Venous insufficiency, Chronic Venous Disease, Pregnancy, IGF-1/PAPP-A/STC-2 pthaway, Wnt/β-catenin canonical pathway

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