Imbalance of Angiogenic and Growth Factors in Placenta in Maternal Hyperhomocysteinemia

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Alexander V. Arutjunyan^1,a*, Gleb O. Kerkeshko¹, Yulia P. Milyutina^1,2, Anastasiia D. Shcherbitskaia^1,3, Irina V. Zalozniaia¹, Anastasiia V. Mikhel¹, Daria B. Inozemtseva¹, Dmitrii S. Vasilev^1,3, Anna A. Kovalenko³, and Igor Yu. Kogan¹

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

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

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

^* To whom correspondence should be addressed.

Received September 23, 2022; Revised December 23, 2022; Accepted January 11, 2023

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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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KEY WORDS: maternal hyperhomocysteinemia, placenta, angiogenic factors, neurotrophins

DOI: 10.1134/S0006297923020098

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