Placental Vascular Development in Pregnancies Complicated by Maternal Diabetes

Abstract

Diabetes in pregnancy is associated with an increased frequency of placental pathology and abnormalities in fetal growth. Placental development is a vital component in perinatal survival and consequently delivery of a healthy infant. However, the relationship between maternal diabetes and poor perinatal outcome remains poorly understood with knowledge gaps in the underlying mechanisms that directly influence placental development in a diabetic environment such that the fetus is at increased risk of placental dysfunction in late pregnancy. The current study sought to characterise structural changes in placentas at term from pregnancies complicated by maternal diabetes in relation to fetal outcome, maternal glycaemic control and maternal levels of angiogenic factors (PlGF). This thesis tested the hypotheses that placental network structure would be different in pregestational diabetes compared to normal pregnancy and that other components of the diabetic environment in utero in early pregnancy may influence placental vascular development. The experiments in this study involved the use of vascular corrosion casting of chorionic plate arteries and veins to quantify assessment of placental vascular networks. Vascular casts were scanned using Micro-CT imaging and software (Avizo 9.40) to generate quantifiable characteristics of the placental vasculature in both normal and pregestational diabetes pregnancies. Following this, key artery and vein network biometric outputs from Micro-CT imaging were related to birthweight, maternal glycaemic control (HbA1c measurement in first and last trimester) and maternal serum PlGF concentration measured at early, mid and late trimesters during pregnancy in women with diabetes. In addition, studies were conducted using a well-established in vitro model of angiogenesis, to investigate the effects of elevated glucose concentration with and without insulin and metformin on network formation. Images of cellular networks were analysed using the ImageJ software with an angiogenesis analyser extension. Fetoplacental artery and venous network structures at delivery were significantly different in pregnancies complicated by pregestational diabetes with decreased length of vessels and reduced vascular volume observed in diabetes. The implications of these vasculature alterations of the placenta on its function were not investigated. Hyperglycaemia might be related to the observations of reduction in arterial volume as poor maternal glycaemic control contributed to reduced arterial and venous vascular volume in diabetes, but venous vascular volume was also reduced in women with good glycaemic control. Reduced vascular volumes in pregestational diabetes were not related to low maternal serum PlGF concentration in the third trimester. The ability of HUVECs to form cellular network structure was inhibited under high glucose environment (hyperglycaemia). Fluctuating level of glucose concentrations also affected endothelial cell behaviour by hindering their ability to form cellular mesh network structures even after switching back to normoglycaemic conditions. In the presence of metformin and pathophysiological concentrations of insulin, HUVECs maintained in medium containing high glucose concentration appeared improved in network formation. This thesis provides compelling evidence indicating that hyperglycaemia and/or other components of the diabetic environment affect fetoplacental vascular development as observed in altered placenta structure at term. Therapies involving metformin provide a promising start to development of tailored clinical interventions for treatment of aberrant fetal growth in maternal diabetes. Future work will investigate mechanisms that underlie structural changes using in vitro models and the implications of altered placenta structure on function.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Aplin (Supervisor), Susan Greenwood (Supervisor) & Jenny Myers (Supervisor)