Oral Presentation 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Preeclampsia Link to Hypoxic Pregnancy (#11)

Wen Tong 1 2 , Kirsty L Brain 1 , Beth J Allison 1 , Kimberley J Botting 1 2 , Youguo Niu 1 2 , Sage G Ford 1 , Peter FB Wooding 1 , Qiang Lyu 1 , Lin Zhang 1 , Katie A O'Brien 1 , Alice P Sowton 1 , Tereza Cindrova-Davies 1 2 , Hong W Yung 1 2 , Graham J Burton 1 2 , Andrew J Murray 1 , Dino A Giussani 1 2
  1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
  2. Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdome

Introduction: Preeclampsia is a significant killer, but underlying mechanisms remain uncertain, precluding plausible intervention. We investigated whether hypoxic pregnancy leading to fetal growth restriction (FGR) in sheep promotes maternal cardiovascular and placental dysfunction, as in preeclampsia.

Methods: Pregnant ewes were exposed to normoxia (N; n=10) or 10% hypoxia (H; n=7) from 105 to 138 days gestational age (dGA; term 145 dGA) in isobaric chambers. At 138 dGA, in vivo uterine artery resistance was assessed by Doppler ultrasonography while maintaining N or H, as appropriate. At post mortem, maternal, fetal and placental biometry was determined and placentomes collected for molecular analysis and mitochondrial respirometry. A separate cohort of pregnant ewes was instrumented at 120 dGA with Transonic flow probes and catheters to record maternal cardiovascular function via a wireless data acquisition system (CamDAS).  Five days later, ewes were exposed to N (n=5) or H (n=5) for 10 days.  Data were compared statistically via the Student’s t test for umpaired data and two-way RM ANOVA.

Results: Hypoxic pregnancy led to FGR and increased the uterine artery pulsatility index (PI; Fig 1 A and B). It also prevented the longitudinal fall in uterine vascular resistance and maternal blood pressure measured in normoxic controls with advancing gestation (Fig 1 C and D). Hypoxic pregnancy increased the expression of the mitochondrial chaperone HSP60, part of the mitochondrial unfolded protein response (UPRmt, Fig 1 E). Hypoxic pregnancy led to a decrease in the mitochondrial fusion protein OPA1 (Fig 2 F) and reduced mitochondrial oxygen consumption dependent on Complex I and b-oxidation (Figure 2 G and H).   

Conclusion:  Hypoxic pregnancy leads to placental oxidative and mitochondrial stress associated with alterations in mitochondrial oxygen consumption and metabolism. These data provide a link between hypoxic pregnancy with a maternal and placental phenotype reminiscent of preeclampsia.

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