Angiogenesis and Novel Therapeutic Drugs in Pre-eclampsia Assessed in a Human Cell-based in Vitro Model

Research output: Book/ReportDoctoral thesis

Abstract

Pre-eclampsia is a condition unique to human pregnancy. It is characterized by new- onset hypertension and widespread endothelial dysfunction. The exact aetiology of pre-eclampsia is unsolved, but knowledge of its pathophysiology has increased in recent decades. Currently, pre-eclampsia is considered as a placental disease. One of the pathogenic mechanisms is thought to be imbalanced angiogenesis in the maternal circulation. That has been found weeks before the onset of clinical disease and has been seen to correlate with the severity of the disease. Angiogenic factors have been widely studied in recent years with the aim of finding a method to predict subsequent pre-eclampsia, or therapeutic targets. So far, the only curative treatment for pre- eclampsia remains delivery of the foetus and placenta.

This thesis covers four studies, in all of which we have utilized a human cell- based tissue model to study angiogenic properties of pre-eclampsia. The vasculogenesis/angiogenesis model was developed in the Finnish Centre for Alternative Methods (FICAM) which is a centre of expertise for alternative methods to animal experimentation.

In the first study, we collected maternal blood and umbilical-cord blood samples from eleven primiparous women with pre-eclampsia and ten primiparous controls in 2011–2014. Maternal blood samples were taken near delivery and umbilical blood samples were taken after childbirth. Sera from pre-eclamptic women strongly inhibited angiogenesis whereas in the control group there was no inhibition. Umbilical blood samples were inhibitory after both pre-eclampsia and normal pregnancy, and there was no difference between the groups.

It the second study, we assessed early gestational angiogenic properties and longitudinal changes in angiogenic capacity of sera from women with healthy and pre-eclamptic pregnancies by using in vitro and immunoassay tests. The study population consisted of six primiparous women who subsequently developed pre- eclampsia and six healthy controls. In the first trimester, maternal sera from both groups had a stimulatory effect on angiogenesis in vitro and levels of angiogenic proteins did not differ between the groups.

The aim of the third and fourth studies was to elucidate the effects of three concentrations of metformin (Study III) and pravastatin (Study IV) on angiogenesis with and without maternal sera. For this we recruited twenty pregnant women in 2017-2018. Maternal serum samples were obtained from women with early-and late- onset pre-eclampsia, intrauterine growth restriction and healthy pregnancies. At therapeutic concentrations, neither of the drugs enhanced angiogenesis. In contrast, metformin at a high concentration had a strong inhibitory effect on angiogenesis in every group. Pravastatin at the lowest concentrations along with maternal sera from early-onset pre-eclamptic pregnancies had a stimulatory effect on angiogenesis in some women.

In conclusion, we showed that a human cell-based vasculogenesis/angiogenesis model can be utilized to study angiogenic properties in pre-eclampsia as well as interactions between maternal sera and therapeutic agents. In addition, the data obtained from the in vitro assay offer a holistic perspective to the angiogenic capacity of serum. In contrast to previous studies, which have hypothesized that metformin and pravastatin therapies restore angiogenic balance in pre-eclampsia, the results of this study suggest that at therapeutic concentrations neither of these drugs improve angiogenesis markedly.
Original languageEnglish
Place of PublicationTampere
PublisherTampere University
ISBN (Electronic)978-952-03-1974-8
ISBN (Print)978-952-03-1973-1
Publication statusPublished - 2021
Publication typeG5 Doctoral dissertation (article)

Publication series

NameTampere University Dissertations - Tampereen yliopiston väitöskirjat
Volume423
ISSN (Print)2489-9860
ISSN (Electronic)2490-0028

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