Placenta-targeted treatment with nMitoQ prevents an endothelin receptor-A pathway cardiac phenotype observed in adult male offspring exposed to hypoxia in utero

Nataliia Hula; Raven Kirschenman; Anita Quon; Floor Spaans; Tom J Phillips; C Patrick Case; Christy-Lynn M Cooke; Sandra T Davidge

doi:10.1152/ajpheart.00238.2023

Placenta-targeted treatment with nMitoQ prevents an endothelin receptor-A pathway cardiac phenotype observed in adult male offspring exposed to hypoxia in utero

Am J Physiol Heart Circ Physiol. 2023 Jul 1;325(1):H136-H141. doi: 10.1152/ajpheart.00238.2023. Epub 2023 May 26.

Authors

Nataliia Hula^{1

2

3}, Raven Kirschenman^{2

3}, Anita Quon^{2

3}, Floor Spaans^{2

3}, Tom J Phillips⁴, C Patrick Case⁵, Christy-Lynn M Cooke^{2

3}, Sandra T Davidge^{1

2

3}

Affiliations

¹ Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
² Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.
³ Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
⁴ Dementia Research Institute, Cardiff University, Cardiff, United Kingdom.
⁵ Musculoskeletal Research Unit, University of Bristol, Bristol, United Kingdom.

PMID: 37235521
DOI: 10.1152/ajpheart.00238.2023

Abstract

Prenatal hypoxia is associated with enhanced susceptibility to cardiac ischemia-reperfusion (I/R) injury in adult offspring, however, the mechanisms remain to be fully investigated. Endothelin-1 (ET-1) is a vasoconstrictor that acts via endothelin A (ET_A) and endothelin B (ET_B) receptors and is essential in maintaining cardiovascular (CV) function. Prenatal hypoxia alters the ET-1 system in adult offspring possibly contributing to I/R susceptibility. We previously showed that ex vivo application of ET_A antagonist ABT-627 during I/R prevented the recovery of cardiac function in prenatal hypoxia-exposed males but not in normoxic males nor normoxic or prenatal hypoxia-exposed females. In this follow-up study, we examined whether placenta-targeted treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ) during hypoxic pregnancies could alleviate this hypoxic phenotype observed in adult male offspring. We used a rat model of prenatal hypoxia where pregnant Sprague-Dawley rats were exposed to hypoxia (11% O₂) from gestational days (GD) 15-21 after injection with 100 μL saline or nMitoQ (125 μM) on GD15. Male offspring were aged to 4 mo and ex vivo cardiac recovery from I/R was assessed. Offspring born from hypoxic pregnancies and treated with nMitoQ had increased cardiac recovery from I/R in the presence of ABT-627 compared with their untreated counterparts where ABT-627 prevented recovery. Cardiac ET_A levels were increased in males born from hypoxic pregnancies with nMitoQ treatment compared with saline controls (Western blotting). Our data indicate a profound impact of placenta-targeted treatment to prevent an ET_A receptor cardiac phenotype observed in adult male offspring exposed to hypoxia in utero.NEW & NOTEWORTHY In this follow-up study, we showed a complete lack of recovery from I/R injury after the application of an ET_A receptor antagonist (ABT-627) in adult male offspring exposed to hypoxia in utero while maternal treatment with nMitoQ during prenatal hypoxia exposure prevented this effect. Our data suggest that nMitoQ treatment during hypoxic pregnancies may prevent a hypoxic cardiac phenotype in adult male offspring.

Keywords: adult male offspring; cardiac ischemia-reperfusion injury; nMitoQ; placenta-targeted treatment; prenatal hypoxia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atrasentan
Endothelin-1
Female
Follow-Up Studies
Hypoxia* / complications
Male
Placenta
Pregnancy
Rats
Rats, Sprague-Dawley
Receptors, Endothelin*

Substances

Receptors, Endothelin
Atrasentan
Endothelin-1

Grants and funding

FS154313/CIHR/Canada