Russian Journal of Woman and Child Health
ISSN 2618-8430 (Print), 2686-7184 (Online)

Placental vasculogenesis and angiogenesis in women undergoing chemotherapy

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DOI: 10.32364/2618-8430-2021-4-1-23-30

Yu.E. Dobrokhotova1, E.I. Borovkova1, A.M. Arutyunyan1, S.Zh. Danelyan2, E.M. Malysheva2, N.V. Zharkov2,3, T.N. Aksenova2

1 Pirogov Russian National Research Medical University, Moscow, Russian Federation

2City Clinical Hospital No. 40, Moscow, Russian Federation

3 I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation

Aim: to study placental vasculogenesis and angiogenesis in women receiving chemotherapy.

Patients and Methods: placental structure was examined in 57 pregnant women aged 22–38 years who were subdivided into 3 groups, i.e., women with malignancies receiving or not receiving chemotherapy and healthy controls. The slices of the central part of placentas collected after childbirth were examined. Immunohistochemistry (IHC) was performed after standard histology. IHC intensity was assessed for CD31 and CD34. In addition to IHC intensity, the number of positive cells per field of view was calculated for VEGF, VEGFR1, and VEGFR2. Mean counts of positive cells separately for epithelial and stromal cells were calculated for eNOS.

Results: in the control group, the maturity of the placental villous tree matched the gestational age. Meanwhile, in 100% of pregnant women with malignancies receiving chemotherapy and in 46.8% of pregnant women with malignancies not receiving chemot herapy, the maturity of the placental villous tree was 2–4 weeks behind the gestational age. IHC revealed no significant differences in the placental concentrations of CD31, CD39, eNOS, VEGF, VEGFR1, and VEGFR2 between women with malignancies not receiving chemotherapy and the controls. In women receiving chemotherapy, IHC intensity and the number of positive cells were twice as high as in the control group. The activity of VEGFR1 and VEGFR2 was 11 times higher and 1.4 times higher, respectively, than in the control group. The mean number of cells expressing VEGFR1 and VEGFR2 per field of view increased by 1.5 times and 1.7 times, respectively. In addition, 1.6-fold reduction in CD31 level and 1.3-fold reduction in CD34 level as well as 1.4-fold increase in epithelial еNOS level and 1.3-fold increase in stromal eNOS level were revealed.

Conclusions: our findings on IHC distribution of the expression of VEGF and its recep-tors in the placental tissue of pregnant women undergoing cytostatic chemotherapy in part illus-trate the processes of the compensation and impaired functioning of the mother-placenta-fetus system in pre-placental hypoxia.

Keywords: angiogenesis, vasculogenesis, vascular growth factor, chemotherapy, hypoxia, placental insufficiency.

For citation: Yu.E. Dobrokhotova, Borovkova E.I., Arutyunyan A.M., Danelyan S.Zh. et al. Placental vasculogenesis and angiogenesis in women undergoing chemotherapy. Russian Journal of Woman and Child Health. 2021;4(1):23–30. DOI: 10.32364/2618-8430-2021-4-1-23-30.

Background

Placental development is a complex multistep process whose efficacy is mainly determined by vasculogenesis and angiogenesis. Vasculogenesis is defined as a process of novel blood vessel formation from mesodermal precursors of endothelial cells (hemangioblasts) that begins at the end of the 3rd week of gestation [1]. Angiogenesis is referred to as the formation of vessels from preexisting structures via elongation, invagination, and capillary budding [2].

Elongation is the lengthening of a vessel via the proliferation of endothelial vessels (non-branching angiogenesis). Invagination and capillary budding are referred to as branching angiogenesis. Invagination is the formation of a new vessel within the lumen of a previous vessel via the migration of endothelial cells while during capillary budding a new lateral branch is generated via lateral growth.

Vasculogenesis and angiogenesis are regulated by cytokines and growth factors [3]. Vascular endothelial growth factor (VEGF) is one of the most important ones [4-6]. It was demonstrated that VEGFR1 and VEGFR2 are expressed in placental syncytiotrophoblast, endothelial cells of placental villus capillaries [7, 8]. VEGF binds with insoluble VEGFR1 (membrane tyrosine kinase receptors) and triggers a cascade of reactions that initiate angiogenesis. Activation of VEGFR2 increases vascular permeability and promotes to migration and proliferation of endothelial cells. The levels of VEGF increase as pregnancy progresses being 5 times greater compared to baseline levels [9]. At late stages of angiogenesis, macrophages, fibroblasts, and smooth muscle cells secrete antiangiogenic factors that prevent migration and proliferation of endothelial cells thus providing optimal balance between angiogenesis and apoptosis of endotheliocytes that is required for normal functioning of the placenta [10, 11].

Immunohistochemistry (IHC) of placentas has demonstrated that VEGF and its receptors (VEGFR1 and VEGFR2) are located only in cytotrophoblast, angiogenic cells, Hofbauer cells, and pre-endothelial cells forming a primitive vascular network. In hypoxia, placental expression of VEGF and VEGFR1 slightly increases [12, 13] while expression of VEGFR2 reduces [14].

Several vasoactive mediators control the vascular tonus of the fetoplacental complex. Among them, nitric oxide (NO) whose synthesis is mediated by endothelial NO synthase (eNOS) is the most important one. The major purpose of NO production is to maintain low vascular resistance in placental arteries via both the paracrine effect and angiogenesis [15, 16]. It was empirically demonstrated that NO is involved much more in angiogenesis than in vasculogenesis. In the 2nd and 3rd trimesters, eNOS is produced in the syncytiotrophoblast. The production of NO by placental NOS in the intervillous lacuna prevents adhesion and aggregation of platelets and relaxes villous smooth muscle cells [17]. IHC demonstrates a 3-fold increase in eNOS expression in placental vascular endothelium in the 3rd trimester of pregnancy compared to other parts of the vascular bed [18]. eNOS induces the proliferation of endothelial cells and angiogenesis. VEGF induces eNOS-dependent synthesis of NO in endotheliocytes by activating VEGFR1 and VEGFR2. It was shown that very high levels of NO prevent angiogenesis while its effects on cell proliferation depend on concentration [19].

Angiogenic T cells (CD31) play an important role in neovascularization [20, 21]. These cells located between vascular endothelial cells provide cell adhesion and regulate endothelial permeability. CD31 characterizes the activity of angiogenesis [22]. Transmembrane CD34 located in placental villi and blood vessels is a marker of early differentiation of hematopoietic precursor cells and endothelial cells [23]. This protein determines vascular density, and its levels correlate with vasculogenesis [24]. Expression of CD34 in the capillaries of cytotrophoblast villi reduces in placental insufficiency, intrauterine growth restriction, and prolonged pregnancy [25]. CD34 and CD31 are used for IHC detection of blood vessels and the evaluation of their tissue density [26].

Chemotherapy during pregnancy is allowed after the 2nd trimester but associated with various risks [27, 28], first of all, placental insufficiency. The placenta is a biological barrier, and all chemotherapeutic agents penetrate by passive or facilitated diffusion and active transport [29]. The rate of penetration is determined by the molecular weight of a drug, its lipophilicity, and its binding with transporter proteins. Chemotherapeutic drugs are partially absorbed by placental tissues whereby reducing drug concentration in fetal blood flow.

Studies on the effects of chemotherapeutic agents on structural and functional changes in the placenta are scarce.

Aim

To study placental vasculogenesis and angiogenesis in women undergoing chemotherapy.

Patients and Methods

This prospective case-control study was approved by the local ethics committee of the Pirogov Russian National Research Medical University. All women have given informed consent to participate in this study. 57 pregnant women were enrolled. Group 1 included 10 pregnant women aged 22-38 years (on average, 29.0 ± 3.81 years) with malignancies who underwent chemotherapy. Group 2 included 32 pregnant women aged 22-39 years (on average, 33.0 ± 3.99 years) with malignancies who did not undergo chemotherapy. Group 3 (control group) included 15 healthy pregnant women aged 23-37 years (on average, 29.0 ± 4.1 years).

In group 1, two women were diagnosed with Hodgkin's lymphoma (stages 2 and 4) during pregnancy. These women underwent 3 and 6 courses of BEACOPP-14 chemotherapy, respectively, at 29, 32, and 35 weeks of gestation and in the postpartum period. 6 women were diagnosed with non-keratinizing squamous cell carcinoma of the cervix (T1аN0M0–T2bN0M0, IА–IB) during pregnancy. Three courses of AUC-5 chemotherapy (docetaxel 75-100 mg/m2 and carboplatin 500 mg) were performed at 26, 29, and 32 weeks of gestation in 3 women and 27, 30, and 33 weeks of gestation in 3 women. Two women were diagnosed with clear cell triple-negative breast cancer (Т3N2M0–T4bN3M1) during pregnancy. Two courses of AC chemotherapy (doxorubicin 80 mg/m2 and cyclophosphamide 800 mg/m2) were performed at 22 and 25 weeks of gestation in 1 woman and 24 and 27 weeks of gestation in 1 woman.

Four women with malignancies who underwent chemotherapy (40%) had a healthy pregnancy. In the 2nd and 3rd trimesters of pregnancy, 3 women (30%) were diagnosed with threatened preterm labor, 3 women (30%) were diagnosed with abnormal uteroplacental blood flow stage IA, 2 women (20%) were diagnosed with intrauterine growth restriction stage 1, and 4 women (40%) were diagnosed with mild-to-moderate anemia.

C-section was performed in all women at 32.1 ± 2.9 weeks of gestation.

In group 2, breast cancer was identified in 6 women. Among them, 2 women were diagnosed with carcinoma in situ, 2 women were diagnosed with triple-negative invasive carcinoma of no special type (T1cN2M0–T4bN1Mx), 1 woman was diagnosed with poorly differentiated infiltrative ductal carcinoma of no special type (T2N0M0), and 1 woman was diagnosed with luminal B apocrine carcinoma (T2NхMx). In 5 women, breast cancer was revealed during pregnancy and in 1 woman, breast cancer was diagnosed in the postpartum period. A doctors' Concilium has established to deliver these women with late preterm pregnancy and to prescribe chemotherapy in the postpartum period.

During pregnancy, 4 women were diagnosed with squamous cell carcinoma in situ of the cervix, and 9 women were diagnosed with invasive squamous cell carcinoma of the cervix (T1bNxM0–T1b2N1M0, IB–IB2). 2 women were diagnosed with clear cell renal cancer (T1bN0M0-T2bN0M0, stage 2) and 2 women were diagnosed with papillary urothelial cell bladder cancer (T1NхM0). In 3 women, pregnancy occurred after non-surgical treatment for highly differentiated endometrial carcinoma (T1аN0M0). 1 woman was diagnosed with mucinous cystadenocarcinoma (T1aN0M0, IА), 1 woman with highly differentiated endometrioid cystadenocarcinoma (T1aN0M0), 1 woman with parotid gland adenocarcinoma (T2N2M0), 1 woman with Hodgkin's lymphoma (stage 1), 1 woman with papillary thyroid cancer (T1аN0M0), and 1 woman with melanoma on the thigh (T2aN0M0). Since no cancer progression was reported during pregnancy, A doctors' Concilium has been established to prescribe chemotherapy after childbirth.

Nine women (28.1%) were diagnosed with anemia, 19 women (59.4%) were diagnosed with threatened preterm labor, and 3 women (9.4%) were diagnosed with placental insufficiency (abnormal uteroplacental blood flow stage IA and II, intrauterine growth restriction stage 2-3).

Vaginal delivery of a full-term newborn occurred in 13 women (40.6%) while C-section was performed in 19 women (59.4%). The average pregnancy length in women who underwent C-section was 37.8 ± 2.19 weeks.

In group 3, vaginal delivery of a full-term newborn occurred in all 15 women (the average pregnancy length was 39.6 ± 1.4 weeks).

Morphology and IHC were performed in the Pathomorphological Department of the City Clinical Hospital No. 40. After delivery, a 2 × 2-cm fragment was excised from the central part of the placenta and fixed in a 10% solution of neutral formalin. After paraffin wax embedding, sections were stained with Mayer's hematoxylin and eosin. Standard histology was followed by IHC of dewaxed sections 4-5 mm thick. Dewaxing, antigen unmasking, and IHC were performed using standard protocols (Leica BOND-MAX). Mouse monoclonal antibodies against CD31 (clone JC70, Cell Marque, dilution 1:100), CD34 (clone QBEnd/10, Cell Marque, dilution 1:100), and VEGF (clone C12, Cloud-Clone Corp., dilution 1:100) and rabbit polyclonal antibodies against VEGFR1 (GeneTex, dilution 1:100), VEGFR2 (GeneTex, dilution 1:100), and eNOS (CloudClone Corp., dilution 1:100) were used as primary antibodies. After the IHC reaction, cell nuclei were stained with Mayer's hematoxylin.

IHC reaction was evaluated using semiquantitative and quantitative methods. IHC staining intensity for CD31 and CD34 was assessed using a 3-point scale (0, negative; 1, weak positive; 2, moderate positive; 3, strong positive). This objective assessment was performed using automated equipment (microspectrophotometers, densitometers, etc.) and applying a common Beer-Lambert Law based on light absorption. In addition to IHC staining intensity, the number of positive cells per field of view (FOV) was calculated for VEGF, VEGFR1, and VEGFR2 (× 200). The number of positive cells in 10 FOV (× 200) and the arithmetical mean were calculated. Mean counts of positive cells separately for epithelial and stromal cells were calculated for eNOS using the same technique.

Statistical analysis was performed using IBM SPSS Statistics 25 software (IBM, USA). Mean values, standard deviation, and standard error were calculated. Considering normal distribution, the intergroup comparison was performed using Student's t-test and χ2 test. Differences were deemed significant if p was less than 0.05.

Results and Discussion

Morphological analysis of the central fragments of placenta collected from 42 women with malignancies and 15 healthy women was performed.

Histologic examination of placenta received from healthy pregnant women (control group) and stained with H&E has demonstrated that the maturity of the placental villous tree matches the gestational age. Moderate compensatory adaptive and involutory dystrophic changes were also seen. Meanwhile, in 10 placentas (100%) of group 1 and 15 placentas (46.8%) of group 2, the maturity of the placental villous tree was 2–4 weeks behind the gestational age. In addition, villous stromal edema of various severity and wide intervillous space were identified in group 1. Villi of large diameter with few capillaries represent the major mass of the villous tree.

Staining intensity and the number of positive cells in trophoblast and vascular endothelium were evaluated by IHC (see Table 1). Staining intensity is a qualitative parameter and the mean count (density) of positive cells is a quantitative parameter that is calculated by the number of positive cells per FOV.

Таблица 1. Экспрессия гликопротеинов, факторов роста и их рецепторов в плаценте Table 1. Placental expression of glycoproteins, growth factors, and their receptors

IHC revealed no significant differences in placental concentrations of CD31, CD39, eNOS, VEGF, VEGFR1, and VEGFR2 between women with malignancies not receiving chemotherapy and the controls (p>0.05).

A significant increase in the levels of VEGF and its receptors was reported in the placentas of women who received chemotherapy. IHC staining intensity and the number of positive cells were twice as high as in the control group. The activity of VEGFR1 and VEGFR2 was 11 times higher and 1.4 times higher, respectively than in the control group. The mean number of cells expressing VEGFR1 and VEGFR2 per FOV increased by 1.5 times and 1.7 times, respectively. These findings are indicative of compensatory response to hypoxia [30, 31]. Hypoxia is accounted for by several factors. First, in pregnant women who received chemotherapy, low levels of CD31 and CD34 (indicators of angiogenesis) were demonstrated by IHC. Therefore, the formation of new vessels (angiogenesis and vasculogenesis) in the placenta of women receiving chemotherapy is not as active as in healthy placenta. Second, in pregnant women with malignancies who received chemotherapy, abnormal uteroplacental blood flow, and low-to-moderate anemia were diagnosed in 30% and 40%, respectively. Abnormal uteroplacental blood flow is presumably accounted for by impaired placental angiogenesis. Meanwhile, anemia is likely to be the result of inhibition of erythropoiesis by chemotherapy (a common complication of chemotherapy) or hemodilution during pregnancy (a physiological process).

The analysis of the correlations of the intensity of the expression of VEGF and its receptors is also of interest. In healthy placentas, lower expression of VEGFR1 and higher expression of VEGFR2 compared to VEGF expression (as demonstrated by IHC) were reported. In pregnant women with malignancies who received chemotherapy, VEGFR1/VEGF intensity ratio was 5.5-times higher compared to the control group and VEGFR2/VEGF intensity ratio was 1.4-times lower compared to the controls (see Figs. 1-3).

Рис. 1. Интенсивность ИГХ-реакции VEGF в тканях плацент в 1-й (А), 2-й (B) и 3-й (C) группах. ×200 Fig. 1. Placental VEGF intensity by IHC in group 1 (A), group 2 (B), and group 3 (C). × 200

Рис. 2. Интенсивность ИГХ-реакции VEGFR1 в тканях плацент в 1-й (А), 2-й (B) и 3-й (C) группах. ×200 Fig. 2. Placental VEGFR1 intensity by IHC in group 1 (A), group 2 (B), and group 3 (C). × 200

Рис. 3. Интенсивность ИГХ-реакции VEGFR2 в тканях плацент в 1-й (А), 2-й (B) и 3-й (C) группах. ×200 Fig. 3. Placental VEGFR2 intensity by IHC in group 1 (A), group 2 (B), and group 3 (C). × 200

CD31 is indicative of angiogenesis (i.e., formation of new vessels from preexisting vessels) and CD34 is indicative of vasculogenesis. A 1.6-fold reduction in CD31 levels and a 1.3-fold reduction in CD34 levels compared to the control group were revealed (see Figs. 4 and 5). These findings suggest that chemotherapeutic agents mostly affect blood vessel branching and capillary bed formation than de novo formation of vessels.

Рис. 4. Экспрессия CD31 в тканях плацент в 1-й (А), 2-й (B) и 3-й (C) группах. ×200 Fig. 4. Placental CD31 expression in group 1 (A), group 2 (B), and group 3 (C). × 200

Рис. 5. Экспрессия CD34 в тканях плацент в 1-й (А), 2-й (B) и 3-й (C) группах. ×200 Fig. 5. Placental CD34 expression in group 1 (A), group 2 (B), and group 3 (C). × 200

Expression of eNOS correlates to the increase in VEGF levels since eNOS generation and NO synthesis are initiated only after VEGF receptor activation. In pregnant women with malignancies who received chemotherapy, a 1.4-fold increase in epithelial еNOS levels and a 1.3-fold increase in stromal eNOS levels were identified (see Fig. 6).

Рис. 6. Интенсивность ИГХ-реакции еNOS в тканях плацент в 1-й (А), 2-й (B) и 3-й (C) группах. ×200 Fig. 6. Placental eNOS intensity by IHC in group 1 (A), group 2 (B), and group 3 (C). × 200

Placental angiogenesis in women undergoing chemotherapy needs further studies involving a larger number of patients to assess the effects of various chemotherapeutic protocols on the placental vascular bed.

Conclusions

Our findings on the IHC of healthy placentas are generally in line with published data on the distribution of VEGF and its receptors [2]. The comparative analysis demonstrates no independent effects of malignancies on angiogenesis and vasculogenesis.

We have demonstrated that angiogenesis without vascular branching predominates in the placentas of women with malignancies receiving chemotherapy. Moreover, more significant expression of VEGF and VEGFR2 was reported compared to healthy placentas. In normal conditions, the binding of VEGF and VEGFR2 activates angiogenesis by enhancing the proliferation and growth of endotheliocytes. In moderate hypoxia, binding of VEGF and VEGFR2 results in the hypercapillarization of intermediate villi via a classic feedback mechanism. This phenomenon is accompanied by a significant expression of VEGF and VEGFR2 in villous endothelial cells. Even though chemotherapy provides conditions for pre-placental hypoxia and is associated with the increased expression of VEGF and VEGFR2, histology revealed the predominance of angiogenesis without vascular branching. These findings are presumably accounted for by the effects of factors and mechanisms preventing VEGF binding with its receptor and, therefore, inhibiting angiogenesis with vascular branching that is typical for hypoxia.

Our findings on IHC distribution of the expression of VEGF and its receptors in the placenta of pregnant women undergoing cytostatic chemotherapy in part illustrate compensatory processes and impaired functioning of the mother-placenta-fetus system in pre-placental hypoxia.


About the authors:

Yuliya E. Dobrokhotova — Doct. of Sci. (Med.), professor, Head of the Department of Obstetrics & Gynecology of the Medical Faculty, Pirogov Russian National Research Medical University; 1, Ostrovityanov str., Moscow, 117437, Russian Federation; ORCID iD 0000-0002-7830-2290.

Ekaterina I. Borovkova — Doct. of Sci. (Med.), professor of the Department of Obstetrics & Gynecology of the Medical Faculty, Pirogov Russian National Research Medical University; 1, Ostrovityanov str., Moscow, 117437, Russian Federation; ORCID iD 0000-0001-7140-262X.

Anna M. Arutyunyan — postgraduate student of the Department of Obstetrics & Gynecology of the Medical Faculty, Pirogov Russian National Research Medical University; 1, Ostrovityanov str., Moscow, 117437, Russian Federation; ORCID iD 0000-0002-6392-5444.

Sonya Zh. Danelyan — Cand. of Sci. (Med.), obstetrician gynecologist of the highest qualification category, Head of the Maternity Hospital, City Clinical Hospital No. 40; 6, Taimyrskaya str., Moscow, 129336, Russian Federation; ORCID iD 0000-0002-8594-6406.

Evgeniya M. Malysheva — Cand. of Sci. (Med.), Head of the Department of Morbid Anatomy, City Clinical Hospital No. 40; 7, Kasatkin str., Moscow, 129301, Russian Federation; ORCID iD 0000-0003-0974-0403.

Nikolai V. Zharkov — Cand. of Sci. (Biol.), biologist of the Centralized Department of Morbid Anatomy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8 Build. 2, Trubetskaya str., Moscow, 119991, Russian Federation; morbid anatomist of the Department of Morbid Anatomy, City Clinical Hospital No. 40; 7, Kasatkin str., Moscow, 129301, Russian Federation; ORCID iD 0000-0001-7183-0456.

Tat’yana N. Aksenova — morbid anatomist of the Department of Morbid Anatomy, City Clinical Hospital No. 40; 7, Kasatkin str., Moscow, 129301, Russian Federation; ORCID iD 0000-0001-6848-0459.

Contact information: Anna M. Arutyunyan, e-mail: annochka21.90@mail.ru. Financial Disclosure: no authors have a financial or property interest in any material or method mentioned. There is no conflict of interests. Received 07.12.2020, revised 30.12.2020, accepted 29.01.2021.



References
1. Rosen L.S. VEGF-targeted therapy: therapeutic potential and recent advances. Oncologist. 2005;10:382–391. DOI: 10.1634/theoncologist.10-6-382.
2. Sokolov D.I. Vasculogenesis and angiogenesis in development of a placenta. Journal of Obstetrics and Women`s Diseases. 2007;56(3):129–133 (in Russ.).
3. Demir R. Expression of VEGF receptors VEFGR-1 and VEGFR-2, angiopoietin receptors Tie-1 and Tie-2 in chorionic villi tree during early pregnancy. Folia Histochem Cytobiol. 2009;47(3):435–445. DOI: 10.2478/v10042-009-0100-5.
4. Qin Liu, Tao Yin, Guoping Wang et al. Vascular endothelial growth receptor 1 acts as a stress-associated protein in the therapeutic response to thalidomide. Exp Ther Med. 2017;14:4263–4271. DOI: 10.3892/etm.2017.5028.
5. Seo-Ho Lee, Byung-Ju Kim, Uh-Hyun Kim. The critical role of uterine CD31 as a post-progesterone signal in early pregnancy. Reproduction. 2017;154:595–605. DOI: 10.1530/REP-17-0419.
6. Kulandavelu S., Whiteley K.J., Bainbridge S.A. et al. Endothelial NO synthase augments fetoplacental blood flow, placental vascularization, and fetal growth in mice. Hypertension. 2013;61:259–266. DOI: 10.1161/HYPERTENSIONAHA.112.201996.
7. Zubzhitskaya L.B., Kosheleva N.G., Shapovalova E.A. et al. Status of placental barrier of women at the influence of exogenous and endogenous factors. Journal of Obstetrics and Women`s Diseases. 2015;64(5):36–47 (in Russ.).
8. Gardner V., Madu C.O., Lu Y. Anti-VEGF therapy in cancer: a double-edged sword. Intech open science, 2017, chapter 19, 385–410. DOI: 10.5772/66763.
9. Al-Hijji J., Andolf E., Laurini R., Batra S. Nitric oxide synthase activity in human trophoblast, term placenta and pregnant myometrium. Reprod Biol Endocrinol. 2003;1(1):51. DOI: 10.1186/1477-7827-1-51.
10. Manolea M.M., Gavrila O.A., Popescu F.C., Novac L. The importance of immunohistochemical evaluation of the vascular changes from the decidua and placenta in recurrent pregnancy loss. Rom J Morphol Embryol. 2012;53(2):363–368.
11. Min-cheol Kang, Seo Jin Park, Hei Jung Kim et al. Gestational loss and growth restriction by angiogenic defects in placental growth factor transgenic mice. Arterioscler Thromb Vasc Biol. 2014;34:2276–2282. DOI: 10.1161/ATVBAHA.114.303693.
12. Krause B.J., Hanson M.A., Casanello P. Role of nitric oxide in placental vascular development and function. Placenta. 2011;32:797–805. DOI: 10.1016/j.placenta.2011.06.025.
13. Helske S., Vuorela P., Carpen O. et al. Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. Mol Hum Reprod. 2001;7(2):205–210. DOI: 10.1093/molehr/7.2.205.
14. Nevo O., Lee D.K., Caniggia I. Attenuation of VEGFR-2 expression by sFlt-1 and low oxygen in human placenta. Plos One. 2013;8(11):e81176. DOI: 10.1371/journal.pone.0081176.
15. Ramırez-Velez R., Bustamante J., Czerniczyniec A. et al. Effect of exercise training on eNOS expression, NO production and oxygen metabolism in human placenta. PLoS One. 2013;8(11):e80225. DOI: 10.1371/journal.pone.0080225.
16. Mackiewicz Z., Dudek E., Glab G. et al. CD34 stem cells in normal placenta tissues and in placenta with intrauterine growth retardation. Acta medica lituanica. 2004;11(2):34–38.
17. Lysyak D.S., Volkova N.N. Pathophysiological mechanisms of placental insufficiency. Far East Medical Journal. 2012;4:134–137 (in Russ.).
18. Sheppard C., Shaw C.E., Li Y. Endothelium-derived nitric oxide synthase protein expression in ovine placental arteries. Biol Reprod. 2001;64:1494–1499. DOI: 10.1095/biolreprod64.5.1494.
19. Volkova E.V., Kopylova Yu.V. The role of vascular growth factors in the pathogenesis of placental insufficiency. Obstetrics, gynecology and reproduction. 2013;7(2):29–33 (in Russ.).
20. Sokolov D.I., Kolobov A.V., Lesnichiya M.V. et al. Role of pro- and antiangiogenic factors in placental development. Medical immunology. 2008;10(4–5):347–352 (in Russ.).
21. Daenen L.G.M., Roodhart J.M.L., van Amersfoort M. et al. Chemotherapy enhances metastasis formation via VEGFR-1-expressing endothelial cells. Cancer Res. 2011;71(22):6976–6985. DOI: 10.1158/0008-5472.CAN-11-0627.
22. Dong-bao Chen, Jing Zheng. Regulation of placental angiogenesis. Manuscript 2013. DOI: 10.1111/micc.12093.
23. Robin C., Bollerot K., Mendes S. et al. Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development. Cell Stem Cell. 2009;5(4):385–395. DOI: 10.1016/j.stem.2009.08.020.
24. Ul`yanina E.V., Fatkullin I.F. Vascular endothelial growth factor role in predicting vascular disorders in pregnant with fetal growth restriction syndrome. Kazan medical journal. 2015;96(2):220–223 (in Russ.).
25. Fedorova M.V., Smirnova T.L. Immunohistochemical differences in the placentas of prolonged and the true post-term pregnancy. Bulletin of the Chuvash University. 2013;3:560–563 (in Russ.).
26. Nefedova N.A., Kharlova O.A., Danilova N.V. et al. Markers of angiogenesis in tumor growth. Archive of pathology. 2016;2:55–62 (in Russ.).
27. Dobrokhotova Yu.E., Borovkova E.I., Arutyunyan A.M. Breast cancer associated with pregnancy. Russian Bulletin of Obstetrician-Gynecologist. 2019;19(4):77–81 (in Russ.).
28. Dobrokhotova Yu.E., Borovkova E.I., Zalesskaya S.A. et al. Chemotherapy during pregnancy: opportunities and risks. Russian bulletin of obstetrician-gynecologist. 2019;19(3):81–85 (in Russ.).
29. Dobrokhotova Yu.E., Borovkova E.I. Obstetric risks of chemotherapy during pregnancy. Gynecology. 2018;6:16–19 (in Russ.).
30. Malamitsi-Puchner A., Boutsikou T., Economou E. et al. Vascular endothelial growth factor and placenta growth factor in intrauterine growth-restricted fetuses and neonates. Mediators Inflamm. 2005;2005(5):293–297. DOI: 10.1155/MI.2005.293.
31. Arutyunyan I.V., Kananykhina E. Yu., Makarov A.V. Role of VEGF-А165 receptors in angiogenesis. Cellular transplantation and tissue engineering. 2013;VIII(1):12–18 (in Russ.).



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