Intergenerational and genetic influence on blood pressure in pregnancy and beyond

Abstract

This thesis examined the role of genetic and intergenerational influence on blood pressure in pregnancy and beyond. Preeclampsia is a hypertensive disorder of pregnancy associated with worldwide maternal and fetal morbidity and mortality. The thesis was conducted in two parts. Part one utilised an animal model to examine the cardiovascular profile of healthy captive baboons across their lifespan. The second part of this thesis investigated the role of genetics in placental dysfunction associated with preeclampsia in humans. This study identified genome-wide changes to DNA methylation profiles in placentas from women with preeclampsia that may be associated with changes in placental development and function. There were 303 gene regions found to be differentially methylated in the placentas from women with preeclampsia when compared to controls, after adjusting for gestational age at delivery. Of these, 214 regions were hypermethylated and 89 were hypomethylated. Pathway analysis revealed significant associations with Wnt signalling, cadherin signalling, cell adhesion and vascular smooth muscle contraction. Of the five gene regions selected, three of them; SPESP1 and NOX5, WNT2, and ALCAM showed significant changes in methylation by pyrosequencing between control and placentas from women with preeclampsia. Subsequently, mRNA expression of SPESP1, NOX5, WNT2 and ALCAM were measured in an independent set of placental samples (Controls, n= 3; Preeclampsia, n = 2). No significant differences in mRNA expression of the genes selected were observed between the two groups. There was aberrant methylation in the gene regions involved in cell adhesion (ALCAM), cell signalling (WNT2) and establishment of pregnancy including fertilisation and implantation (SPESP1). The research presented in this thesis contributes to our understanding of the physiological and molecular mechanisms involved in the development of and impact that preeclampsia has on both the mother and baby and provides opportunities to improve the monitoring and care of both the mothers and offspring that are affected by this disease.

Date of Award	2015
Original language	English