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Gestational Intermittent Hypoxia Induces Sex-Specific Impairment in Endothelial Mechanisms and Sex Steroid Hormone Levels in Male Rat Offspring

Abstract

Obstructive sleep apnea (OSA) is highly prevalent during gestation and is linked with adverse fetal outcomes. We examined whether gestational intermittent hypoxia (GIH), the main feature of OSA, leads to sex-specific alterations in cardiovascular function and vascular mechanisms in the offspring. Pregnant rats exposed to intermittent hypoxia or ambient air from gestation days 10 to 21 and their offspring were used for the study. GIH exposure did not affect water and food intake in dams. Compared to controls, the male and female offspring born to GIH dams were smaller in weight by 14% and 12%, respectively, and exhibited catch-up growth. Cardiac function was not affected in either GIH males or females. At 12 weeks of age, blood pressure was increased in GIH males, but not GIH females, compared to their control counterparts. While mesenteric arterial contractile responses to phenylephrine and endothelin were unaffected in GIH males and females, relaxation response to acetylcholine was reduced in GIH males but not GIH females. Relaxation to sodium nitroprusside was unaffected in both GIH males and females. Total eNOS expression was not affected, but phospho(Ser1177)-eNOS levels were decreased in GIH males. eNOS expression and its phosphorylation status were unaffected in GIH females. Serum testosterone and estradiol levels were higher in GIH males but were unaltered in GIH females. Together, these findings suggest that GIH leads to a sex-specific increase in blood pressure in adult male offspring with blunted endothelium-mediated relaxation, decreased eNOS activity, and elevated sex steroid hormone levels.

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Availability of Data and Material

Data available within the article. Raw data that support the findings of this study are available from the corresponding author, upon request.

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Funding

Supported by the National Institutes of Health (NIH) R01HL119869 and R01HL134779 (S.K.) and R01HL142752 (JJW and TLB).

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Sathish Kumar conceptualized and designed the study. Ruolin Song, Jay S. Mishra, and Sri Vidya Dangudubiyyam contributed to material preparation, data collection, analysis, and interpretation. Ruolin Song and Jay S. Mishra wrote the first draft of the manuscript. Kathleen M. Antony, Tracy L. Baker, and Jyoti J. Watters provided scientific input in the experimental design and critically reviewed the manuscript. All authors edited the manuscript and approved the final version.

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Correspondence to Sathish Kumar.

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Song, R., Mishra, J., Dangudubiyyam, S. et al. Gestational Intermittent Hypoxia Induces Sex-Specific Impairment in Endothelial Mechanisms and Sex Steroid Hormone Levels in Male Rat Offspring. Reprod. Sci. (2021). https://doi.org/10.1007/s43032-021-00739-4

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Keywords

  • Intermittent hypoxia
  • Pregnancy
  • Blood pressure
  • Fetal programming
  • Endothelium
  • eNOS