DOI: https://doi.org/10.22263/2312-4156.2020.2.35
Pauliukevich A.N., Belyaeva L.Eu.
The system of nitric oxide production in rats which have undergone prenatal stress
Vitebsk State Order of Peoples’ Friendship Medical University, Vitebsk, Republic of Belarus
Vestnik VGMU. 2020;19(2):35-43.
Abstract.
Objectives. To assess the level of nitric oxide (NO) production, intensity of the lipid peroxidation (LPO) processes in the blood serum and the low grade inflammation level as well as to measure the blood pressure (BP) in rats whose mothers were exposed to the impact of stressors during pregnancy.
Material and methods. Outbred pregnant rats (180-220 g) were devided into 2 groups, 10 animals in each. Pregnant rats out of «stress» group underwent the influence of different types of stress factors: fasting during the day, contact with cats’ excrements during the day and 20 minute immobilization in water (t=23±2); while pregnancy in the second group of rats developed in normal conditions («control»). Serum concentration of nitrates / nitrites (NO3-/NO2-), endothelial and inducible isoforms of NO-synthase (eNOS and iNOS, respectively), asymmetric dimethylarginine (ADMA), diene conjugates (DC), malondialdehyde (MDA), C-reactive protein (hsCRP) and BP were determined in 3-month-old offspring.
Results. Stressors exposure in the prenatal period led to the increase in blood pressure, iNOS, hsCRP and MDA concentration without any statistically significant changes of the level of NO3-/NO2- in the blood serum of both male and female rats. In male rats (but not females), whose mothers were exposed to stress during pregnancy, the decrease in the level of eNOS and the increase in the content of ADMA and DC in the blood serum were revealed.
Conclusions. Disorders of the NO synthesis system in prenatally stressed rats have sexual features. In 3-month offspring of rats, which were exposed to the impact of stressors during pregnancy, lipid peroxidation intensity and blood pressure were increased and systemic low-grade inflammation developed.
Key words: prenatal stress, nitric oxide, NO-synthase, asymmetric dimethylarginine, lipid peroxidation, systemic low grade inflammation, arterial blood pressure.
The sources of financing: funds allocated within the frames of the theme task of State Research Programs (GPNI) of the Republic of Belarus «To evaluate the delayed sequel of the prenatal stress to the coronary vessels tension and to substantiate the methods for revealed disturbances prevention».
References
1. Furchgott RF. Endothelium-derived relaxing factor: discovery, early studies, and identification as nitric oxide. Biosci Rep. 1999 Aug;19(4):235-51. doi: http://dx.doi.org/10.1023/a:1020537506008
2. Daiber A, Xia N, Steven S, Oelze M, Hanf A, Kröller-Schön S, et al. New therapeutic implications of endothelial nitric oxide synthase (eNOS) function/dysfunction in cardiovascular disease. Int J Mol Sci. 2019 Jan;20(1). pii: E187. doi: http://dx.doi.org/10.3390/ijms20010187
3. Barker DJ. In utero programming of chronic disease. Clin Sci (Lond). 1998 Aug;95(2):115-28.
4. Belyaeva LE, Fedchenko AN, Lazuko SS, Ligetskaya IV, Orekhova NI. Peculiarities of disorders of NO-dependent mechanisms of regulation of the vascular tone of the heart vessels of rats undergoing the action of stressors in the prenatal period. Vestn VGMU. 2017;16(2):58-69. (In Russ.)
5. Mir SA. An improved zinc reduction method for direct determination of nitrate in presence of nitrite. As J Chem. 2007;19(7):5703-10.
6. Gavrilov VB, Gavrilova AR, Khmara NF. Measurement of plasma diene conjugates by ultraviolet absorption of heptane and isopropyl extracts. Lab Delo. 1988;(2):60-4. (In Russ.)
7. Andreeva LI, Kozhemyakin LA, Kishkun AA. Modification of the method for determining lipid peroxides in the test with thiobarbituric acid. Lab Delo. 1988;(11):41-3. (In Russ.)
8. Kuznetsova AS, Gozhenko AI, Kuznetsova ES, Shukhtin VV, Kuznetsova EN, Kuznetsov SG. Endothelium. Physiology and Pathology: monografiia. Odessa, Ukraine: Feniks; 2018. 284 р. (In Russ.)
9. Fulton DJ. Transcriptional and posttranslational regulation of eNOS in the endothelium. Adv Pharmacol. 2016;77:29-64. doi: http://dx.doi.org/10.1016/bs.apha.2016.04.001
10. Chan Y, Fish JE, D'Abreo C, Lin S, Robb GB, Teichert AM, et al. The cell-specific expression of endothelial nitric-oxide synthase: a role for DNA methylation. J Biol Chem. 2004 Aug;279(33):35087-100.
11. Fish JE, Matouk CC, Rachlis A, Lin S, Tai SC, D'Abreo C, et al. The expression of endothelial nitric-oxide synthase is controlled by a cell-specific histone code. J Biol Chem. 2005 Jul;280(26):24824-38.
12. Lee DY, Chiu JJ. Atherosclerosis and flow: roles of epigenetic modulation in vascular endothelium. J Biomed Sci. 2019 Aug;26(1):56. doi: http://dx.doi.org/10.1186/s12929-019-0551-8
13. Anavi S, Tirosh O. iNOS as a metabolic enzyme under stress conditions. Free Radic Biol Med. 2020 Jan;146:16-35. doi: http://dx.doi.org/10.1016/j.freeradbiomed.2019.10.411
14. Chan GC, Fish JE, Mawji IA, Leung DD, Rachlis AC, Marsden PA. Epigenetic basis for the transcriptional hyporesponsiveness of the human inducible nitric oxide synthase gene in vascular endothelial cells. J Immunol. 2005 Sep;175(6):3846-61. doi: http://dx.doi.org/10.4049/jimmunol.175.6.3846
15. Fulton MD, Brown T, Zheng YG. The biological axis of protein arginine methylation and asymmetric dimethylarginine. Int J Mol Sci. 2019 Jul;20(13). pii: E3322. doi: http://dx.doi.org/10.3390/ijms20133322
16. Chen K, Pittman RN, Popel AS. Nitric oxide in the vasculature: where does it come from and where does it go? A quantitative perspective. Antioxid Redox Signal. 2008 Jul;10(7):1185-98. doi: http://dx.doi.org/10.1089/ars.2007.1959
17. Liu X, Xu X, Shang R, Chen Y. Asymmetric dimethylarginine (ADMA) as an important risk factor for the increased cardiovascular diseases and heart failure in chronic kidney disease. Nitric Oxide. 2018 Aug;78:113-120. doi: http://dx.doi.org/10.1016/j.niox.2018.06.004
18. Tain YL, Hsu CN. Toxic dimethylarginines: asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Toxins (Basel). 2017 Mar;9(3). pii: E92. doi: http://dx.doi.org/10.3390/toxins9030092
19. Wang F, Xiong R, Feng S, Lu X, Li H, Wang S. Association of circulating levels of ADMA with carotid intima-media thickness in patients with CKD: a systematic review and meta-analysis. Kidney Blood Press Res. 2018;43(1):25-33. doi: http://dx.doi.org/10.1159/000486743
20. Eklund CM. Proinflammatory cytokines in CRP baseline regulation. Adv Clin Chem. 2009;48:111-36. doi: http://dx.doi.org/10.1016/s0065-2423(09)48005-3
21. Jašarević E, Howard CD, Misic AM, Beiting DP, Bale TL. Stress during pregnancy alters temporal and spatial dynamics of the maternal and offspring microbiome in a sex-specific manner. Sci Rep. 2017 Mar;7:44182. doi: http://dx.doi.org/10.1038/srep44182
22. Shanmugam N, Figarola JL, Li Y, Swiderski PM, Rahbar S, Natarajan R. Proinflammatory effects of advanced lipoxidation end products in monocytes. Diabetes. 2008 Apr;57(4):879-88. doi: http://dx.doi.org/10.2337/db07-1204
23. Gourdy P, Guillaume M, Fontaine C, Adlanmerini M, Montagner A, Laurell H, et al. Estrogen receptor subcellular localization and cardiometabolism. Mol Metab. 2018 Sep;15:56-69. doi: http://dx.doi.org/10.1016/j.molmet.2018.05.009
24. Monsalve E, Oviedo PJ, García-Pérez MA, Tarín JJ, Cano A, Hermenegildo C. Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells. Cardiovasc Res. 2007 Jan;73(1):66-72. doi: http://dx.doi.org/10.1016/j.cardiores.2006.09.020
25. Bourque SL, Gragasin FS, Quon AL, Mansour Y, Morton JS, Davidge ST. Prenatal hypoxia causes long-term alterations in vascular endothelin-1 function in aged male, but not female, offspring. Hypertension. 2013 Oct;62(4):753-8. doi: http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.01516
26. Zhu X, Gao Q, Tu Q, Zhong Y, Zhu D, Mao C, et al. Prenatal hypoxia enhanced angiotensin II-mediated vasoconstriction via increased oxidative signaling in fetal rats. Reprod Toxicol. 2016 Apr;60:21-8. doi: http://dx.doi.org/10.1016/j.reprotox.2016.01.001
27. Ponzio BF, Carvalho MH, Fortes ZB, do Carmo Franco M. Implications of maternal nutrient restriction in transgenerational programming of hypertension and endothelial dysfunction across F1-F3 offspring. Life Sci. 2012 Apr;90(15-16):571-7. doi: http://dx.doi.org/10.1016/j.lfs.2012.01.017
28. Wlodek ME, Westcott K, Siebel AL, Owens JA, Moritz KM. Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats. Kidney Int. 2008 Jul;74(2):187-95. doi: http://dx.doi.org/10.1038/ki.2008.153
29. Wyrwoll CS, Mark PJ, Waddell BJ. Developmental programming of renal glucocorticoid sensitivity and the rennin-angiotensin system. Hypertension. 2007 Sep;50(3):579-84. doi: http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.091603
30. Dagan A, Gattineni J, Cook V, Baum M. Prenatal programming of rat proximal tubule Na+/H+ exchanger by dexamethasone. Am J Physiol Regul Integr Comp Physiol. 2007 Mar;292(3):R1230-5. doi: http://dx.doi.org/10.1152/ajpregu.00669.2006
Information about authors:
Pauliukevich A.N. – Master of Medical Sciences, senior lecturer of the Chair of Pathologic Physiology, Vitebsk State Order of Peoples’ Friendship Medical University;
Belyaeva L.E. – Candidate of Medical Sciences, associate professor, head of the Chair of Pathologic Physiology, Vitebsk State Order of Peoples’ Friendship Medical University.
Correspondence address: Republic of Belarus, 210009, Vitebsk, 27 Frunze ave., Vitebsk State Order of Peoples’ Friendship Medical University, Chair of Pathologic Physiology. E-mail: Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра. – Lyudmila E. Belyaeva.
