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Imbalance of Angiogenic and Growth Factors in Placenta in Maternal Hyperhomocysteinemia

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Abstract

Numerous studies have shown that various adverse factors of different nature and action mechanisms have similar negative influence on placental angiogenesis, resulting in insufficiency of placental blood supply. One of the risk factors for pregnancy complications with placental etiology is an increased level of homocysteine in the blood of pregnant women. However, the effect of hyperhomocysteinemia (HHcy) on the development of the placenta and, in particular, on the formation of its vascular network is at present poorly understood. The aim of this work was to study the effect of maternal HHcy on the expression of angiogenic and growth factors (VEGF-A, MMP-2, VEGF-B, BDNF, NGF), as well as their receptors (VEGFR-2, TrkB, p75NTR), in the rat placenta. The effects of HHcy were studied in the morphologically and functionally different maternal and fetal parts of the placenta on the 14th and 20th day of pregnancy. The maternal HHcy caused increase in the levels of oxidative stress and apoptosis markers accompanied by an imbalance of the studied angiogenic and growth factors in the maternal and/or fetal part of the placenta. The influence of maternal HHcy in most cases manifested in a decrease in the protein content (VEGF-A), enzymatic activity (MMP-2), gene expression (VEGFB, NGF, TRKB), and accumulation of precursor form (proBDNF) of the investigated factors. In some cases, the effects of HHcy differed depending on the placental part and stage of development. The influence of maternal HHcy on signaling pathways and processes controlled by the studied angiogenic and growth factors could lead to incomplete development of the placental vasculature and decrease in the placental transport, resulting in fetal growth restriction and impaired fetal brain development.

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Abbreviations

BDNF:

brain-derived neurotrophic factor

FPP:

fetal part of placenta

Hcy:

homocysteine

HHcy:

hyperhomocysteinemia

MDA:

malondialdehyde

MMP:

matrix metalloproteinase

LPO:

lipid peroxidation

MPP:

maternal part of placenta

NGF:

nerve growth factor

OS:

oxidative stress

PE:

preeclampsia

SOD:

superoxide dismutase

VEGF:

vascular endothelial growth factor

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Funding

This work was financially supported by the Russian Science Foundation, grant 22-15-00393 (investigation of the effects of HHcy on molecular and cellular processes of placenta development), and by the State Budget Project of the Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, project no. 1021062812133-0-3.2.2 (investigation of the parameters of oxidative stress and apoptosis in placenta).

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Authors and Affiliations

  1. D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, 199034, St. Petersburg, Russia

    Alexander V. Arutjunyan, Gleb O. Kerkeshko, Yulia P. Milyutina, Anastasiia D. Shcherbitskaia, Irina V. Zalozniaia, Anastasiia V. Mikhel, Daria B. Inozemtseva, Dmitrii S. Vasilev & Igor Yu. Kogan

  2. St. Petersburg State Pediatric Medical University, Russian Ministry of Health, 194100, St. Petersburg, Russia

    Yulia P. Milyutina

  3. I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223, St. Petersburg, Russia

    Anastasiia D. Shcherbitskaia, Dmitrii S. Vasilev & Anna A. Kovalenko

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  1. Alexander V. Arutjunyan
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  2. Gleb O. Kerkeshko
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Contributions

I. Yu. Kogan, A. V. Arutjunyan – conceptualization and supervision of work; I. V. Zalozniaia, Yu. P. Milyutina, A. D. Shcherbitskaia, A. V. Mikhel, D. B. Inozemtseva – conducting experiments; Yu. P. Milyutina, A. D. Shcherbitskaia, I. V. Zalozniaia, A. V. Mikhel, D. B. Inozemtseva, G. O. Kerkeshko, D. S. Vasiliev, A. A. Kovalenko – processing of the results; A. V. Arutjunyan, G. O. Kerkeshko, Yu. P. Milyutina, A. D. Shcherbitskaia – discussion of the results of the study; A. V. Arutjunyan, G. O. Kerkeshko – writing the text of the paper; A. V. Arutjunyan, G. O. Kerkeshko, Yu. P. Milyutina, A. D. Shcherbitskaia – editing of the final text of the paper.

Corresponding author

Correspondence to Alexander V. Arutjunyan.

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The authors declare no conflicts of interest in financial or any other sphere. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Arutjunyan, A.V., Kerkeshko, G.O., Milyutina, Y.P. et al. Imbalance of Angiogenic and Growth Factors in Placenta in Maternal Hyperhomocysteinemia. Biochemistry Moscow 88, 262–279 (2023). https://doi.org/10.1134/S0006297923020098

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