Cardiovascular disease remains the leading cause of death worldwide. One factor known to alter the risk of developing cardiovascular disease is the environment experienced by the developing fetus, through the developmental programming of disease. In particular, fetal hypoxia has been frequently linked with reduced cardiac function, hypertension and fibrosis once offspring reach adulthood. A greater understanding of the mechanisms causing this cardiac programming will direct future interventions, with the potential to target the cardiovascular disease burden before birth. Recently, mitochondrial biology has been implicated as a major driver of developmental programming. As mitochondria are both highly sensitive to hypoxia and crucially linked with the pathogenesis of cardiovascular disease, we predicted that fetal hypoxia could programme multiple aspects of mitochondrial function, with resultant adverse effects on cardiac function. In this doctoral research, two models of fetal hypoxia were used to simulate different pregnancy complications; 1) early-onset mild hypoxia (13% oxygen from day 6â20 of gestation which models high-altitude pregnancies, and 2) late-onset moderate hypoxia (10.5% oxygen from day 15â20 of gestation) which models placental insufficiency/pre-eclampsia. We also investigated the protective effects of maternal melatonin treatment to alleviate offspring cardiac dysfunction. To identify the immediate effects of fetal hypoxia on cardiac mitochondrial function, oxidative capacity and hydrogen peroxide (HâOâ) were measured in hypoxic fetal rats in the 13% oxygen model. We found that oxygen consumption was reduced whilst HâOâ production was increased in hypoxic male fetuses only, with females unaffected. Additionally, maternal antioxidant treatment was unable to prevent the reductions in mitochondrial function, despite reaching the fetus. The long-term effects of fetal hypoxia on the mitochondria of the heart were explored in adult offspring from hypoxic pregnancies. We observed reductions in oxygen consumption, increases in HâOâ production, and a decrease in calcium retention capacity in the moderate hypoxic group. Interestingly, this latter finding could explain the increase in ischemia-reperfusion (IR) injury we and others have observed in adult offspring from hypoxic pregnancies. Indeed, we found that components of the mitochondrial permeability transition pore (the MPTP, a crucial driver of IR injury) were increased in fetally-hypoxic offspring. Together, this data suggests the MPTP can be programmed by fetal hypoxia, which may underlie the increase in IR injury frequently observed. Collectively this data suggests that mitochondria are a key target of fetal hypoxia in the programming of cardiovascular disease. These findings can be used to design therapeutics and prevent programming during fetal life. Continued exploration of developmental programming of the MPTP is warranted considering the universal nature of the MPTP, its role in cell death and the potential ecological consequences of MPTP programming in other vertebrate species.
Date of Award | 1 Aug 2024 |
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Original language | English |
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Awarding Institution | - The University of Manchester
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Supervisor | Delvac Oceandy (Supervisor) & Gina Galli (Supervisor) |
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- ischemia-reperfusion
- mitochondrial permeability transition pore
- developmental programming
- hypoxia
- mitochondria
Programming of cardiac mitochondrial function by developmental hypoxia
Smith, K. (Author). 1 Aug 2024
Student thesis: Phd