Prenatal Hypoxia and the Impact of Maternal Antioxidant (MitoQ) Treatment on Developmental Programming of Cardiovascular Disease

• Author / Creator

  Aljunaidy, Mais

• Cardiovascular disease is the primary cause of morbidity and mortality worldwide. Prenatal hypoxia (due to placental or maternal hypoxia) is an established risk factor for cardiovascular disease. Hypoxia in pregnancy can lead to intrauterine growth restriction (IUGR; defined as a fetus who does not reach its genetic growth potential) and to an increase in offspring susceptibility to develop cardiovascular disease later in life, a concept known as developmental programming of cardiovascular disease. This PhD project focusses on assessing the effect of hypoxia in pregnancy on maternal vascular function, fetal development and on offspring cardiovascular function later in life in both males and females separately. I also aimed to propose an intervention to improve offspring cardiovascular health in complicated pregnancy. As placental oxidative stress is important in the pathophysiology of many pregnancy complications including IUGR and developmental programming, the mitochondrial antioxidant MitoQ loaded onto nanoparticles (nMitoQ) was proposed herein as an intervention to prevent placental oxidative stress and optimally prevent IUGR and fetal programming of cardiovascular disease. Nanoparticles were used to prevent MitoQ from crossing the placental barrier to the fetus in order to avoid risking direct fetal exposure to the antioxidant treatment.
  In this thesis, an established rat model of maternal hypoxia was used. Maternal vascular function was assessed using both in vivo and ex vivo techniques. Fetal body weight was measured after euthanizing the dams. Hypoxia in pregnancy increased maternal blood pressure and caused vascular bed-dependent alterations in maternal vascular function (mesenteric artery versus uterine artery). Furthermore, hypoxia in pregnancy caused a reduction in uterine artery resistance index and IUGR in the fetuses.
  To assess the effect of maternal hypoxia and nMitoQ treatment on developmental programming, a similar animal model but with a shorter period of maternal hypoxic exposure was used (our laboratory has previously assessed the phenotype of offspring cardiovascular function in this animal model). nMitoQ (125 µM) was intravenously injected on GD 15 just before animal exposure to hypoxia and at the same day for the control (dams that stayed in normoxia all over the pregnancy period). In one set of animals, rats were euthanized near term to assess pregnancy outcome, placental oxidative stress, and fetal cardiac development. Cultured medium was prepared and used to assess the effect of placental secreted factors on normal cardiomyocyte growth in male and female fetuses separately. In another set of animals, dams were allowed to give birth and male and female offspring were assessed at 7 and 13 months of age for in vivo cardiac function and ex vivo vascular function.
  Hypoxia in pregnancy led to IUGR and to an increase in placental oxidative stress and relative heart weight to body weight (cardiac hypertrophy) in both male and female fetuses. However, hypoxia led to an increased cardiomyocyte size in only male but not female fetuses. Factors released from placentas of hypoxic dams did not alter normal cardiomyocyte growth. nMitoQ treatment prevented placental oxidative stress in both male and female fetuses. nMitoQ prevented IUGR and prevented cardiac hypertrophy in only female fetuses. However, nMitoQ rescued cardiomyocyte growth, which was increased in male fetuses due to maternal hypoxia.
  In young (7 months) and aged (13 months) male and female offspring, maternal hypoxia led to sex-dependent cardiovascular dysfunction. This includes changes in cardiac morphology, signs of diastolic, and systolic dysfunction and abnormal vascular responses to vasoconstriction and vasorelaxation. nMitoQ treatment partly improved cardiovascular function in offspring of both sexes. For example, in hypoxic dams nMitoQ improved systolic function in aged female offspring compared to the nMitoQ untreated controls; and increased sensitivity to vasorelaxation in aged male and female offspring from normoxic and hypoxic dams.
  In conclusion, this thesis has elucidated factors that play an important role in the pathophysiology of IUGR and developmental programming of cardiovascular disease in male and female offspring. This thesis as well showed that targeting antioxidant treatment to the placenta can impact fetal body weight, fetal cardiac development and offspring cardiovascular function in adult life, suggesting that interventions do not necessarily need to target the fetus to improve fetal outcome. This project helped in setting the stage for future studies about employing nanoparticles to deliver interventions to specific targets during pregnancy to improve offspring cardiovascular function in complicated pregnancy.

• Subjects / Keywords

  • IUGR
  • preeclampsia
  • DOHaD
  • cardiovasuclar
  • MitoQ
  • antioxidant
  • nanoparticles
  • placenta
  • hypoxia

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3K931N9N

• License

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