The Long-Term Effects of Prenatal Hypoxia on Coronary Artery Function of the Male and Female Offspring

Nataliia Hula; Ricky Liu; Floor Spaans; Mazhar Pasha; Anita Quon; Raven Kirschenman; Christy-Lynn M Cooke; Sandra T Davidge

doi:10.3390/biomedicines10123019

The Long-Term Effects of Prenatal Hypoxia on Coronary Artery Function of the Male and Female Offspring

Biomedicines. 2022 Nov 23;10(12):3019. doi: 10.3390/biomedicines10123019.

Authors

Nataliia Hula^{1

2}, Ricky Liu^{1

2}, Floor Spaans², Mazhar Pasha^{1

2}, Anita Quon², Raven Kirschenman², Christy-Lynn M Cooke², Sandra T Davidge^{1

2}

Affiliations

¹ Department of Physiology, University of Alberta, Edmonton, AB T6G 2R3, Canada.
² Department of Obstetrics and Gynecology, Women and Children's Health Research Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada.

Abstract

Prenatal hypoxia predisposes the offspring to the development of cardiovascular (CV) dysfunction in adult life. Using a rat model, we assessed the effect of prenatal hypoxia on vasoconstrictive and vasodilative mechanisms in left anterior descending coronary arteries of 4- and 9.5-month-old offspring. Endothelium-dependent relaxation to methylcholine and vasoconstriction responses to endothelin-1 (ET-1) were assessed by wire myography. Prenatal hypoxia impaired endothelium-dependent vasodilation in 4- and 9.5-month-old offspring. Inhibition of nitric oxide (NO) synthase prevented coronary artery relaxation in all groups. Inhibition of prostaglandin H synthase (PGHS) improved relaxation in prenatally hypoxic males and tended to improve vasorelaxation in females, suggesting that impaired vasodilation was mediated via increased PGHS-dependent vasoconstriction. An enhanced contribution of endothelium-dependent hyperpolarization to coronary artery vasodilation was observed in prenatally hypoxic males and females. No changes in endothelial NO synthase (eNOS) and PGHS-1 expressions were observed, while PGHS-2 expression was decreased in only prenatally hypoxic males. At 4 months, ET-1 responses were similar between groups, while ET_B inhibition (with BQ788) tended to decrease ET-1-mediated responses in only prenatally hypoxic females. At 9.5 months, ET-1-mediated responses were decreased in only prenatally hypoxic females. Our data suggest that prenatal hypoxia has long-term similar effects on the mechanisms of impaired endothelium-dependent vasodilation in coronary arteries from adult male and female offspring; however, coronary artery contractile capacity is impaired only in prenatally hypoxic females. Understanding the mechanistic pathways involved in the programming of CV disease may allow for the development of therapeutic interventions.

Keywords: cardiovascular dysfunction; coronary artery function; developmental origins of health and disease (DOHaD); endothelial dysfunction; endothelin-1 (ET-1); offspring; pregnancy complications; prenatal hypoxia; sex differences.

Grants and funding

This research was funded by a foundation grant from the Canadian Institutes of Health Research (FS154313) and by the Women and Children’s Health Research Institute (WCHRI) through the generosity of the Stollery Children’s Hospital Foundation and the Alberta Women’s Health Foundation. S.D. is a former Tier 1 Canada Research Chair in Maternal and Perinatal Cardiovascular Health and a Distinguished University Professor at the University of Alberta. N.H. was supported by a Stefan and Pelagia Wychowanec Graduate Scholarship and a Motyl Graduate Studentship in Cardiac Sciences from the University of Alberta. M.P. was supported by a WCHRI Graduate Studentship award and Faculty of Medicine and Dentistry 75th Anniversary Award from the University of Alberta.