Intrauterine growth restriction does not lead to pronounced changes in the regulation of arterial contractile responses in rats in the early postnatal period

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Abstract

Intrauterine growth retardation (IUGR) is one of the most common pathologies of pregnancy. As a result of this pathology, the functioning of many systems, including the cardiovascular system, is disrupted. In adult animals who have suffered IUGR, the contribution of procontractile mechanisms regulating vascular tone (for example, the Rho-kinase signaling pathway) increases, and the contribution of anticontractile mechanisms (for example, endothelial NO), on the contrary, decreases, which can lead to vasospasm and impaired blood supply to organs. Since NO and Rho-kinase have a pronounced vasomotor role in early postnatal ontogenesis, the purpose of this work was to assess the influence of IUGR on the contribution of these mechanisms to the regulation of arterial contractile responses in early postnatal ontogenesis. IUGR was modeled by limiting the amount of food consumed by females (by 50%) from the 11th day of pregnancy until birth. In offspring aged 11 - 12 days, the reactions of the isolated saphenous artery were studied in isometric mode, and the content of mRNA and proteins of interest in this artery was also assessed. IUGR did not lead to a change in the reactivity of the arteries of the offspring to the α1-adrenergic receptor agonist methoxamine. The increase in contractile responses to methoxamine in the presence of the NO-synthase inhibitor L-NNA, as well as the expression levels of eNOS (mRNA and protein) and arginase-2 (mRNA) were not changed in the arteries of IUGR rats, while the sensitivity of the arteries to the exogenous NO donor DEA /NO was higher in IUGR compared to control rat pups. Despite the relatively low content of RhoA and Rho-kinase II proteins in the arterial tissue of rat pups from the IUGR group, the decrease in contractile responses under the influence of the Rho-kinase inhibitor Y27632 was equally pronounced in the arteries of rat pups from two experimental groups. Thus, IUGR, caused by maternal nutritional restriction during pregnancy, does not lead to pronounced changes in the regulation of systemic vascular tone in the early postnatal period.

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About the authors

А. А. Shvetsova

Lomonosov Moscow State University

Email: Dina.Gaynullina@gmail.com
Russian Federation, Moscow

Е. К. Selivanova

Lomonosov Moscow State University; ChemRar Research and Development Institute

Email: Dina.Gaynullina@gmail.com
Russian Federation, Moscow; Khimki, Moscow Region

L. D. Shilova

Lomonosov Moscow State University

Email: Dina.Gaynullina@gmail.com
Russian Federation, Moscow

О. S. Tarasova

Lomonosov Moscow State University; Institute of Biomedical Problems of the Russian Academy of Sciences

Email: Dina.Gaynullina@gmail.com
Russian Federation, Moscow; Moscow

D. К. Gaynullina

Lomonosov Moscow State University

Author for correspondence.
Email: Dina.Gaynullina@gmail.com
Russian Federation, Moscow

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2. Fig. 1. Intrauterine growth retardation (IUGR) does not change the reactivity of the subcutaneous artery of 11–12-day-old offspring to the α1-adrenoreceptor agonist methoxamine. The first concentration-effect relationships for methoxamine in the arteries of 11–12-day-old rats in the Control (CON) and IUGR (IUGR) groups are shown. The numbers in brackets indicate the number of animals.

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3. Fig. 2. Intrauterine growth retardation (IUGR) does not change the anticonstrictor contribution of NO in the saphenous artery of 11–12-day-old offspring. (a) Second concentration-effect relationships for methoxamine in the saphenous artery of CON and IUGR rats obtained in the presence of the NO synthase inhibitor L-NNA (100 μM) or an equivalent volume of solvent (H2O, 50 μl). (b) Concentration-effect relationships for the NO donor DEA/NO in the saphenous artery of CON and IUGR rats in the presence of the NO synthase inhibitor L-NNA (100 μM). Numbers in brackets indicate the number of animals. * p < 0.05 (two-way ANOVA for repeated measures).

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4. Fig. 3. Intrauterine growth retardation (IUGR) does not change the proconstrictor contribution of Rho kinase in the saphenous artery of 11- to 12-day-old offspring. (a) Second concentration-effect relationships for methoxamine in the saphenous artery of CON and IUGR rats obtained in the presence of the Rho kinase inhibitor Y27632 (3 μM) or an equivalent volume of solvent (H2O). (b) Second concentration-effect relationships for methoxamine in the saphenous artery of CON and IUGR rats obtained in the presence of the NO synthase inhibitor L-NNA (100 μM) or L-NNA together with Y27632. Numbers in brackets indicate the number of animals. * p < 0.05 (two-way ANOVA for repeated measures).

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5. Fig. 4. Intrauterine growth retardation (IUGR) does not affect the expression of Nos3 (eNOS) and Arg2 (arginase-2) mRNA in the saphenous artery of 11–12-day-old offspring. Relative expression levels of Nos3 (a) and Arg2 (b) mRNA in the saphenous artery of rat pups from the Control (CON) and IUGR (IUGR) groups. Expression values ​​are normalized to the geometric mean of expression of three reference genes (Gapdh, Rplp0, Rn18s) and are expressed as a percentage of the mean in the Control group. Numbers in brackets indicate the number of animals. Data are presented as the mean and standard error of the mean.

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6. Fig. 5. Relative protein content of eNOS (a), RhoA (b), and Rho-kinase II (c) in the saphenous artery of 11–12-day-old rats of the Control (CON) and IUGR (IUGR) groups. Values ​​are normalized to the content of the reference protein GAPDH and are expressed as a percentage of the median (a, b) or the mean (c) in the Control group. Data are presented as median and interquartile range (a, b) or mean and standard error of the mean (c). Numbers in parentheses indicate the number of animals. # p < 0.05 (nonparametric Mann–Whitney test), * p < 0.05 (unpaired Student's t-test).

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