Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB334

Poster Communications

The mitochondria-targeted antioxidant MitoQ prevents the programming of cardiovascular dysfunction by developmental hypoxia in sheep

K. J. Botting1, K. L. Skeffington1, Y. Niu1, B. J. Allison1, K. L. Brain1, N. Itani1, C. Beck1, A. Logan2, M. Murphy2, D. A. Giussani1

1. Physiology, Development & Neuroscience, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom. 2. Mitochondrial Biology Unit, Medical Research Council, Cambridge, United Kingdom.


  • Figure 1. MitoQ content in maternal and fetal tissues (A). Birth weight (B), diastolic arterial pressure in adulthood (C), femoral vascular conductance in response to either SNP infusion (D; represented by grey bar; 15 minute means; B=baseline, SNP=infusion, R=recovery) or LNAME bolus (E; minute means) and in vitro femoral artery relaxation to increasing SNP concentration (F). P<0.05; 2-way ANOVA for effect of Hypoxia (*) and MitoQ (Ψ).

Introduction: Chronic fetal hypoxia programmes cardiovascular dysfunction via oxidative stress (1). In rodents, maternal treatment of hypoxic pregnancies with the antioxidant vitamin C is protective, however, only at concentration incompatible with human clinical translation (2,3). Here, we show in sheep that MitoQ may be a suitable alternative therapeutic candidate. Methods: Singleton pregnant ewes with an indwelling femoral artery and vein catheter (surgically implanted at 100 days gestation; term ~145; anaesthesia induced with 15ml Alfaxan i.v. and maintained with 2% isoflurane with 1:3 N2O:O2 mechanical ventilation) were exposed to normoxia (N) or hypoxia (H; 10% O2) with or without maternal MitoQ treatment (Q; 1.2mg/kg/day i.v. in saline) during the last third of gestation (105-138 days; n= N:10, H:10, HQ:6, NQ:8). After natural delivery, offspring were maintained until 9 months, and then chronically instrumented (anaesthetic protocol as above) with vascular catheters and a femoral flow probe to determine in vivo cardiovascular function followed by ex vivo peripheral endothelial function (wire myography). Data were analysed by 2-way ANOVA with repeated measures, as appropriate. Results: Maternal MitoQ treatment crossed the placenta and reached therapeutic concentration (4) in the fetus (A). Offspring of hypoxic pregnancy were smaller at birth (B) and hypertensive at adulthood (N: 90±2; H: 98±2; HQ: 91±2; NQ: 89±3mmHg, P<0.05) with elevated systolic (N: 114±2; H: 126±2; HQ: 118±4; NQ: 114±4mmHg; P<0.05) and diastolic pressure in vivo (C). Maternal MitoQ in hypoxic pregnancy restored the programmed hypertension in adult offspring. Adult offspring from MitoQ pregnancies showed increased NO bioavailability evidenced by a greater increase in femoral vascular conductance (FVC) in response to SNP in vivo (2.5μg/kg/min i.a.; D) and a greater fall in FVC to NO blockade with LNAME in vivo (100mg/kg i.a.; E). Maternal MitoQ in hypoxic pregnancy also restored the programmed impaired femoral artery dilator sensitivity to SNP in vitro (F). Conclusion: Maternal MitoQ treatment in pregnancy complicated by chronic fetal hypoxia protects against programmed cardiovascular dysfunction in adulthood. The mechanism underlying this protection involves programmed increases in NO bioavailability and sensitivity in the cardiovascular system of the adult offspring.

Where applicable, experiments conform with Society ethical requirements