Long-term effects of prenatal hypoxia on cardiomyocyte function

Abstract

It is well known that lifestyle and genetics play a role in the development of cardiovascular diseases. Comparatively less is known about the impact of the intrauterine environment on the adult cardiovascular system. Studies show a clear link between prenatal insults and the development of different diseases. Insults such as maternal nutrition, stress and low oxygen (hypoxia) can lead to the developmental programming of heart structure and function, causing long-lasting effects on the cardiovascular system. This study aimed to develop a mouse model prenatal hypoxia and determine the effects on the adult cardiac phenotype. In particular, the study focussed on the effects of prenatal hypoxia on structure and function, as well as cardiomyocyte intracellular Ca2+ handling. Pregnant mice were subjected to 14% oxygen between gestational days 6-18. This level of hypoxia did not affect the dams’ body weight, food or water intake. Newborn offspring showed no signs of intrauterine growth restriction. Prenatal hypoxia had no effect on adult offspring whole heart function or response to ischaemia and reperfusion. Mitochondrial content was unaffected by prenatal hypoxia, but both adult males and females from hypoxic pregnancies showed decreased cristae density, compared to their normoxic counterparts. Males from hypoxic pregnancies exhibited no differences in mitochondrial enzyme activity or mitochondrial oxygen consumption. However, prenatal hypoxia led to increased ROS production in most of the male mitochondrial respiratory states. In females, complex I and II activity were decreased while complex IV activity was increased in offspring from hypoxic pregnancies. In addition, mitochondrial respiration was increased and ROS production was decreased in most respiratory states. Prenatal hypoxia also had effects on intracellular Ca2+ handling; increased Ca2+ clearance capabilities were observed in adult females and increased SERCA 2a protein abundance in males from hypoxic pregnancies. In summary, we showed prenatal hypoxia had different effects in adult male and female offspring with regards to Ca2+ handling and mitochondrial function.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andy Trafford (Supervisor) & Gina Galli (Supervisor)