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Perinatal hypoxia augments contractile impact of NADPH oxidase-derived ROS in early postnatal rat arteries

Pediatric Research (2024)Cite this article

Abstract

Background

 Reactive oxygen species (ROS), including those produced by NADPH oxidase (NOX), play an important vasomotor role, especially at early postnatal period. Mechanisms for regulating vascular tone can change significantly due to neonatal asphyxia and accompanying hypoxia. We tested the hypothesis that normobaric hypoxia (8% O2) for 2 h at the second day of life changes the functional contribution of NOX-derived ROS to the regulation of agonist-induced contraction in early postnatal rats.

Methods

We studied saphenous arteries from 11- to 14-day-old male offspring using isometric myography and Western blotting and assessed the content of biochemical parameters in blood serum.

Results

 The values of main biochemical parameters in blood serum and the protein content of NOXs and superoxide dismutases in arterial tissue did not differ between “Control” and “Hypoxia” pups. The NOX inhibitor VAS2870 equally reduced the contractile responses of arteries to α1-adrenoceptor agonist methoxamine in “Control” and “Hypoxia” pups, but its effect was more pronounced in the arteries from “Hypoxia” pups when vasocontraction was evoked by the agonist of thromboxane A2 receptors U46619.

Conclusion

 Perinatal hypoxia at the second day of life increases procontractile influence of NOX-derived ROS to the regulation of U46619-induced vasocontraction in the systemic arteries at early postnatal ontogenesis.

Impact

  • Nothing is known about programming effects of perinatal hypoxia, including birth asphyxia, on the ROS-mediated regulation of contraction in systemic arteries of early postnatal organism.

  • 2-h normobaric hypoxia (8% O2) in rats at the second day of life increases the procontractile contribution of NOX-produced ROS to the regulation of U46619-induced vasocontraction in the systemic arteries at early postnatal ontogenesis.

  • This fact may serve as a risk factor for the development of various disorders at later developmental stages and should be considered regarding the therapy for newborns who have suffered neonatal asphyxia.

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Fig. 1: Influence of perinatal hypoxia at the age of 2 days on the contribution of ROS, produced by NADPH-oxidase, to the regulation of methoxamine- and U46619-induced vasocontraction in arteries of 11–14-day-old rat pups.
Fig. 2: Perinatal hypoxia at the age of 2 days does not affect the protein content of main isoforms of NOX and SOD in saphenous arteries of 11–14-day-old rat pups.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Gaynullina, D. K., Schubert, R. & Tarasova, O. S. Changes in endothelial nitric oxide production in systemic vessels during early ontogenesis—A key mechanism for the perinatal adaptation of the circulatory system. Int. J. Mol. Sci. 20, 1–12 (2019).

    Article  Google Scholar 

  2. Shvetsova, A. A., Gaynullina, D. K., Tarasova, O. S. & Schubert, R. Remodeling of arterial tone regulation in postnatal development: focus on smooth muscle cell potassium channels. Int. J. Mol. Sci. 22, 5413 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Shvetsova, A. A., Gaynullina, D. K. & Tarasova, O. S. The role of reactive oxygen species in the regulation of blood vessel tone in perinatal and early postnatal ontogenesis. J. Evol. Biochem. Physiol. 59, 2210–2227 (2023).

    Article  Google Scholar 

  4. Morecroft, I. & MacLean, M. R. Developmental changes in endothelium-dependent vasodilation and the influence of superoxide anions in perinatal rabbit pulmonary arteries. Br. J. Pharmacol. 125, 1585–1593 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Belik, J., Jankov, R. P., Pan, J. & Tanswell, A. K. Peroxynitrite inhibits relaxation and induces pulmonary artery muscle contraction in the newborn rat. Free Radic. Biol. Med. 37, 1384–1392 (2004).

    Article  PubMed  CAS  Google Scholar 

  6. Shvetsova, A. A. et al. Reactive oxygen species augment contractile responses of saphenous artery in 10-15-day-old but not adult rats: Substantial role of NADPH oxidases. Free Radic. Biol. Med. 216, 24–32 (2024).

    Article  PubMed  CAS  Google Scholar 

  7. Knock, G. A. NADPH oxidase in the vasculature: expression, regulation and signalling pathways; role in normal cardiovascular physiology and its dysregulation in hypertension. Free Radic. Biol. Med. 145, 385–427 (2019).

    Article  PubMed  CAS  Google Scholar 

  8. Shvetsova, A. A. et al. Perinatal hypoxia weakens anticontractile influence of NO in rat arteries during early postnatal period. Pediatr. Res. 95, 1758–1763 (2024).

  9. Dennis, K. E. et al. NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, 596–607 (2009).

    Article  Google Scholar 

  10. Zhu, X. et al. Prenatal hypoxia enhanced angiotensin II-mediated vasoconstriction via increased oxidative signaling in fetal rats. Reprod. Toxicol. 60, 21–28 (2016).

    Article  PubMed  CAS  Google Scholar 

  11. Ortiz, M., Loidl, F. & Vázquez-Borsetti, P. Transition to extrauterine life and the modeling of perinatal asphyxia in rats. WIREs Mech. Dis. 14, 1–16 (2022).

    Google Scholar 

  12. Mach, M., Dubovický, M., Navarová, J., Brucknerová, I. & Ujházy, E. Experimental modeling of hypoxia in pregnancy and early postnatal life. Interdiscip. Toxicol. 2, 28–32 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ahearne, C. E. Short and long term prognosis in perinatal asphyxia: an update. World J. Clin. Pediatr. 5, 67 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Rainaldi, M. A. & Perlman, J. M. Pathophysiology of birth asphyxia. Clin. Perinatol. 43, 409–422 (2016).

    Article  PubMed  Google Scholar 

  15. Yang, X., Salminen, W. F. & Schnackenberg, L. K. Current and emerging biomarkers of hepatotoxicity. Curr. Biomarler Find. 2, 43–55 (2012).

    CAS  Google Scholar 

  16. Blank, M. et al. Review of Qualification Data for Biomarkers of Nephrotoxicity Submitted by the Predictive Safety Testing Consortium. (2009).

  17. Arndt, T. P. & Boone, L. I. Clinical Pathology of the Rat. The Laboratory Rat 3rd edn https://doi.org/10.1016/B978-0-12-814338-4.00005-2 (Elsevier Inc., 2020).

  18. Štulcová, B. Postnatal development of cardiac output distribution measured by radioactive microspheres in rats. Neonatology 32, 119–124 (1977).

    Article  Google Scholar 

  19. Sofronova, S. I. et al. Endothelial nitric oxide weakens arterial contractile responses and reduces blood pressure during early postnatal development in rats. Nitric Oxide 55–56, 1–9 (2016).

    Article  PubMed  Google Scholar 

  20. Mochalov, S. V. et al. Higher Ca2+-sensitivity of arterial contraction in 1-week-old rats is due to a greater Rho-kinase activity. Acta Physiol. 12, e13044 (2018).

    Article  Google Scholar 

  21. Shvetsova, A. A. et al. TASK‐1 channel blockade by AVE1231 increases vasocontractile responses and BP in 1‐ to 2‐week‐old but not adult rats. Br. J. Pharmacol. 177, 5148–5162 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Mulvany, M. J. & Halpern, W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ. Res. 41, 19–26 (1977).

    Article  PubMed  CAS  Google Scholar 

  23. Borzykh, A. A. et al. Voluntary wheel exercise training affects locomotor muscle, but not the diaphragm in the rat. Front. Physiol. 13, 1–14 (2022).

    Article  Google Scholar 

  24. Olivencia, M. A. et al. Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice. Br. J. Pharmacol. 180, 2361–2376 (2023).

    Article  PubMed  CAS  Google Scholar 

  25. Oliveras-Salvá, M. et al. rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Mol. Neurodegener. 8, 44 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Piano, I. et al. Myriocin effect on Tvrm4 retina, an autosomal dominant pattern of retinitis pigmentosa. Front. Neurosci. 14, 372 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ding, B.-Y. et al. Knockdown of NADPH oxidase 4 reduces mitochondrial oxidative stress and neuronal pyroptosis following intracerebral hemorrhage. Neural Regen. Res. 18, 1734–1742 (2022).

    PubMed Central  Google Scholar 

  28. Wiggers, G. A. et al. Cerebrovascular endothelial dysfunction induced by mercury exposure at low concentrations. Neurotoxicology 53, 282–289 (2016).

    Article  PubMed  CAS  Google Scholar 

  29. Zemanovic, S. et al. Dynamic phosphorylation of the C terminus of Hsp70 regulates the mitochondrial import of SOD2 and redox balance. Cell Rep. 25, 2605–2616 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Gutziet, O. et al. Maternal N-acetyl-cysteine prevents neonatal hypoxia-induced brain injury in a rat model. Int. J. Mol. Sci. 22, 1–12 (2021).

    Article  Google Scholar 

  31. Sukhanova, I. A. et al. Gender-dependent changes in physical development, BDNF content and GSH redox system in a model of acute neonatal hypoxia in rats. Behav. Brain Res. 350, 87–98 (2018).

    Article  PubMed  CAS  Google Scholar 

  32. Sukhanova, I. A. et al. Early-life N-arachidonoyl-dopamine exposure increases antioxidant capacity of the brain tissues and reduces functional deficits after neonatal hypoxia in rats. Int. J. Dev. Neurosci. 78, 7–18 (2019).

    Article  PubMed  CAS  Google Scholar 

  33. Herrera, E. A. et al. High-altitude chronic hypoxia during gestation and after birth modifies cardiovascular responses in newborn sheep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, 2234–2240 (2007).

    Article  Google Scholar 

  34. Williams, S. J., Campbell, M. E., Mcmillen, I. C. & Davidge, S. T. Differential effects of maternal hypoxia or nutrient restriction on carotid and femoral vascular function in neonatal rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, 360–367 (2005).

    Article  Google Scholar 

  35. Moretta, D. et al. Long-term high-altitude hypoxia and alpha adrenoceptor-dependent pulmonary arterial contractions in fetal and adult sheep. Front. Physiol. 10, 1032 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gilbert, R. D., Maruko, K. & Stiffel, V. M. The effect of long-term hypoxia on tension and intracellular calcium responses following stimulation of the thromboxane A2 receptor in the left anterior descending coronary artery of fetal sheep. Reprod. Sci. 16, 364–372 (2009).

    Article  PubMed  Google Scholar 

  37. Garcia, F. C., Stiffel, V. M., Pearce, W. J., Zhang, L. & Gilbert, R. D. Ca(2+) sensitivity of fetal coronary arteries exposed to long-term, high-altitude hypoxia. J. Soc. Gynecol. Investig. 7, 161–166 (2000).

    Article  PubMed  CAS  Google Scholar 

  38. Long, W. E. N., Zhang, L. & Longo, L. D. Fetal and adult cerebral artery K ATP and K Ca channel responses to long-term hypoxia. J. Appl. Physiol. 92, 1692–1701 (2002).

    Article  PubMed  CAS  Google Scholar 

  39. Shvetsova, A. A. et al. Vascular effects of perinatal hypoxia in the early postnatal period in rats. J. Evol. Biochem. Physiol. 59, 800–808 (2023).

    Article  CAS  Google Scholar 

  40. Tsai, M. H. & Jiang, M. J. Reactive oxygen species are involved in regulating α1- adrenoceptor-activated vascular smooth muscle contraction. J. Biomed. Sci. 17, 1–10 (2010).

    Article  Google Scholar 

  41. Chakraborti, S. et al. Role of protein kinase C in NADPH oxidase derived O2 -mediated regulation of Kv – LVOCC axis under U46619 induced increase in [Ca2+] i in pulmonary smooth muscle cells. Arch. Biochem. Biophys. 487, 123–130 (2009).

    Article  PubMed  CAS  Google Scholar 

  42. Gupte, S. A. et al. Peroxide generation by p47 phox -Src activation of Nox2 has a key role in protein kinase C-induced arterial smooth muscle contraction. Am. J. Physiol. Hear. Circ. Physiol. 296, 1048–1057 (2009).

    Article  Google Scholar 

  43. Rehman, A. U., Dugic, E., Benham, C., Lione, L. & Mackenzie, L. S. Selective inhibition of NADPH oxidase reverses the over contraction of diabetic rat aorta. Redox Biol. 2, 61–64 (2014).

    Article  PubMed  CAS  Google Scholar 

  44. Snetkov, V. A. et al. Superoxide differentially controls pulmonary and systemic vascular tone through multiple signalling pathways. Cardiovasc. Res. 89, 214–224 (2011).

    Article  PubMed  CAS  Google Scholar 

  45. Knock, G. A. et al. Superoxide constricts rat pulmonary arteries via Rho-kinase-mediated Ca2+ sensitization. Free Radic. Biol. Med. 46, 633–642 (2009).

    Article  PubMed  CAS  Google Scholar 

  46. Somlyo, A. P. & Somlyo, A. V. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol. Rev. 83, 1325–1358 (2003).

    Article  PubMed  CAS  Google Scholar 

  47. Nobe, K. & Paul, R. J. Effects of Rho-related kinase and protein kinase C inhibition on force and intracellular Ca2+. Circ. Res. 88, 1283–1290 (2001).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank Dr. E. A. Sebentsova and Dr. N. G. Levitskaya for providing access for facility to model hypoxia. The part of equipment used in the study was provided by MSU within the framework of federal project “The development of infrastructure for science and education” (Agreement No 161).

Funding

This work was supported by the Russian Science Foundation (Grant N 23-25-00056).

Author information

Author notes

  1. These authors contributed equally: Dina K. Gaynullina, Anastasia A. Shvetsova.

Authors and Affiliations

  1. Department of Human and Animal Physiology, Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, Russia

    Valentina S. Shateeva, Sofia D. Simonenko, Margarita A. Khlystova, Ekaterina K. Selivanova, Dina K. Gaynullina & Anastasia A. Shvetsova

  2. ChemRar Research and Development Institute, Khimki, Russia

    Ekaterina K. Selivanova

  3. Laboratory of Exercise Physiology, State Research Center of the Russian Federation-Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, Russia

    Anna A. Borzykh

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Contributions

Conceptualization and experimental design (D.K.G., A.A.Sh.), data collection (V.S.Sh., S.D.S., M.A.Kh., E.K.S., A.A.B., D.K.G., A.A.Sh.), data processing (V.S.Sh., D.K.G., A.A.Sh.), manuscript draft writing (D.K.G., A.A.Sh.).

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Correspondence to Anastasia A. Shvetsova.

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Shateeva, V.S., Simonenko, S.D., Khlystova, M.A. et al. Perinatal hypoxia augments contractile impact of NADPH oxidase-derived ROS in early postnatal rat arteries. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03466-z

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