Thesis (M. Biotech.)--Flinders University, Cardiovascular Medicine and Centre for Neuroscience, Cardiovascular Neuroscience Group. / Typescript bound. Includes bibliographical references: (leaves 117-125) Also available electronically.

Piglets that are born with low viability have increased mortality during early life, result in increased labor by personnel and potential animal welfare concerns. Producers focused on improving ovulation rates with the outcome of increased number of piglets with the average of piglets born increasing from 8.0 pigs/litter/sow to 10.3 pigs/litter/sow (NASS, 2016). This may not be advantageous, as number of piglets born per litter increased the weight of each piglet decreased. It is hypothesized this is due to decreased uterine blood flow available per piglet in larger litters, resulting in lower viability piglets at birth. Two studies with the intent of improving uterine blood flow will be discussed. The first study will investigate how pharmaceuticals could enhance uterine blood flow in the gilt. The second study will discuss the postnatal outcome of offspring, who experienced greater umbilical blood flows, born from dams that were exercised during gestation.

In pregnancy, the maternal cardiovascular and placental circulation undergoes structural and functional changes to accommodate the growing fetus, but the mechanisms involved are not fully understood. Nitric oxide (NO) increases in normal pregnancy and lack of NO has been implicated in pregnancy related complications, preeclampsia and fetal growth restriction. Thus, the objective of the thesis was to determine if cardiovascular, uteroplacental and fetoplacental changes observed in human pregnancy also occur in mice and to assess the obligatory role of eNOS in mediating these changes. I showed that like humans, mice exhibit increases in maternal cardiac output, stroke volume, plasma volume, and uterine arterial blood flow, and a transient decrease in arterial pressure during pregnancy. Importantly, I showed that endothelial nitric oxide synthase (eNOS) plays an important role in promoting the progressive increase in maternal cardiac chamber dimensions and output and the enlargement of the aorta during pregnancy in mice. Another novel finding was that eNOS plays an important role in remodeling of the uterine and umbilical vasculatures during pregnancy. The remodeling of the uterine vasculatures, including the uterine and spiral arteries, were blunted in the eNOS KO mice with ko fetuses (KO(ko)) and this likely contributed to elevated vascular resistance and reduced perfusion of the uterine circulation during pregnancy. Impaired spiral artery remodeling may be caused by a deficiency in decidual uterine natural killer cells. Fetal placental vascularization was also impaired in eNOS KO(ko) mice, which likely increased vascular resistance and thereby reduced fetoplacental perfusion. Reduced vascularization may be due to decreased VEGF mRNA and protein expression in KO(ko) placentas. Decreased perfusion in both the uterine and umbilical circulations most likely contributed to elevated placental and fetal hypoxia in the eNOS KO(ko) mice. Interestingly, despite placental hypoxia, eNOS KO(ko) mice do not show the classical signs of preeclampsia including hypertension and proteinuria nor are maternal plasma sFlt1 levels elevated. Nevertheless, eNOS KO(ko) pups are growth restricted at term, and this is mainly due to the fetal genotype. These findings suggest that eNOS plays an essential role during pregnancy in remodeling of the maternal heart, aorta, and uterine and umbilical vasculatures thereby augmenting blood flow to the maternal and fetal sides of the placenta and thereby promoting fetal growth in mice.

In pregnancy, the maternal cardiovascular and placental circulation undergoes structural and functional changes to accommodate the growing fetus, but the mechanisms involved are not fully understood. Nitric oxide (NO) increases in normal pregnancy and lack of NO has been implicated in pregnancy related complications, preeclampsia and fetal growth restriction. Thus, the objective of the thesis was to determine if cardiovascular, uteroplacental and fetoplacental changes observed in human pregnancy also occur in mice and to assess the obligatory role of eNOS in mediating these changes. I showed that like humans, mice exhibit increases in maternal cardiac output, stroke volume, plasma volume, and uterine arterial blood flow, and a transient decrease in arterial pressure during pregnancy. Importantly, I showed that endothelial nitric oxide synthase (eNOS) plays an important role in promoting the progressive increase in maternal cardiac chamber dimensions and output and the enlargement of the aorta during pregnancy in mice. Another novel finding was that eNOS plays an important role in remodeling of the uterine and umbilical vasculatures during pregnancy. The remodeling of the uterine vasculatures, including the uterine and spiral arteries, were blunted in the eNOS KO mice with ko fetuses (KO(ko)) and this likely contributed to elevated vascular resistance and reduced perfusion of the uterine circulation during pregnancy. Impaired spiral artery remodeling may be caused by a deficiency in decidual uterine natural killer cells. Fetal placental vascularization was also impaired in eNOS KO(ko) mice, which likely increased vascular resistance and thereby reduced fetoplacental perfusion. Reduced vascularization may be due to decreased VEGF mRNA and protein expression in KO(ko) placentas. Decreased perfusion in both the uterine and umbilical circulations most likely contributed to elevated placental and fetal hypoxia in the eNOS KO(ko) mice. Interestingly, despite placental hypoxia, eNOS KO(ko) mice do not show the classical signs of preeclampsia including hypertension and proteinuria nor are maternal plasma sFlt1 levels elevated. Nevertheless, eNOS KO(ko) pups are growth restricted at term, and this is mainly due to the fetal genotype. These findings suggest that eNOS plays an essential role during pregnancy in remodeling of the maternal heart, aorta, and uterine and umbilical vasculatures thereby augmenting blood flow to the maternal and fetal sides of the placenta and thereby promoting fetal growth in mice.