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In vivo mitochondria‐targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy

Published version
Peer-reviewed

Repository DOI


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Authors

Wang, Zhongchao 
Nuzzo, Anna Maria 
Spiroski, Ana‐Mishel 
Skeffington, Katie L 

Abstract

jats:secjats:titleAbstract</jats:title>jats:pGestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide‐dependent mechanisms and stimulation of large conductance Cajats:sup2+</jats:sup>‐activated Kjats:sup+</jats:sup>‐channels. Maternal jats:italicin vivo</jats:italic> oral treatment with the mitochondria‐targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6–20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13–14% Ojats:sub2</jats:sub>) pregnancy ± daily maternal MitoQ treatment (500 µjats:scm</jats:sc> in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13‐dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Cajats:sup2+</jats:sup>‐activated Kjats:sup+</jats:sup>‐channel activator NS1619 and ACh via increased nitric oxide‐dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria‐targeted therapy against adverse changes in uterine artery structure and function in high‐risk pregnancy. <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/tjp15950-gra-0001-m.png">jats:alt-textimage</jats:alt-text></jats:graphic></jats:boxed-text></jats:p></jats:sec>jats:secjats:titleKey points</jats:title>jats:p<jats:list list-type="bullet"> jats:list-itemjats:pDysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude.</jats:p></jats:list-item> jats:list-itemjats:pSuch complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy.</jats:p></jats:list-item> jats:list-itemjats:pHere, we show in a rodent model of gestational hypoxia that jats:italicin vivo</jats:italic> oral treatment of the mitochondria‐targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria‐targeted therapy against adverse changes in uterine artery structure and function in high‐risk pregnancy.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec>

Description

Publication status: Published

Keywords

chronic hypoxia, fetal growth restriction, uterine PI, pre‐eclampsia

Journal Title

The Journal of Physiology

Conference Name

Journal ISSN

0022-3751
1469-7793

Volume Title

Publisher

Wiley
Sponsorship
British Heart Foundation (RG/17/8/32924, PG/14/5/30547)
Medical Research Council UK (MC_UU_00028/4)
Wellcome Trust Investigator (220257/Z/20/Z)