title: Vascular damage in pre-eclampsia: the role of endothelial dysfunction
Creators: name: Boswell, Fiona
Publisher: name: University of Glasgow
Year: 1997
Subjects: subject: Pre-eclampsia, blood vessels, endothelium, pathophysiology.

description: Pre-eclampsia is a multisystem disorder specific to pregnant women and is the major cause of maternal death in the United Kingdom today. The common pathophysiological feature of virtually all manifestations of pre-eclampsia is vascular endothelial dysfunction. This probably results from poor placental perfusion due to defective trophoblast invasion. Platelets and neutrophils play a role in the pathophysiological process; recruitment of these cells is mediated by cell adhesion molecule expression. Intrauterine growth restriction (lUGR) is often associated with pre-eclampsia. It too is associated with neutrophil activation. The hypothesis examined in this thesis was that cell adhesion molecule expression, potential markers of endothelial damage and neutrophil activation, was increased in pre-eclampsia and lUGR. The following studies were performed: 1. Circulating concentrations of cell adhesion molecules were measured in normal and pre-eclamptic pregnancies. 2. Cell adhesion molecule mRNA and protein expression were determined in placentae from normal, pre-eclamptic and lUGR pregnancies, 3. Circulating concentrations of cytokines, known to activate neutrophils, were measured in normal and pre-eclamptic pregnancy and 4. The effect of the cytokine IL-6 on the expression of the cell adhesion molecules VCAM-2 and E-Selectin on human umbilical vein endothelial cells was determined. Circulating concentrations of the cell adhesion molecules VCAM-1 and E- Selectin were increased in the maternal circulation of women with pre-eclampsia compared to normal pregnant controls. We found a difference in the expression of E- Selectin between plasma and serum suggesting that the wide range of concentrations of E-Selectin between patients may require large numbers of patients to show a significant trend. We found a higher expression of E-Selectin in serum compared to plasma in normal pregnant patients suggesting that more E-Selectin is shed into serum, after the activation of cells, due to clotting. Immunostaining for platelet endothelial cell adhesion molecule (PECAM) and intercellular adhesion molecule-1 (ICAM-1) was localised mainly to the endothelium of the stem villi, intermediate villi, terminal villi and decidual vessels. ICAM-1 staining was also evident in the stroma and fetal membranes. The placentae sections were negative for VCAM-1 and E-Selectin immunostaining. PECAM, ICAM-1 and ICAM-2 mRNA were all detectable in normal and pre-eclamptic placentae but E-Selectin and VCAM-2 mRNA were undetectable. There were no significant differences in the cell adhesion molecule mRNA expression or immunostaining in pregnancies complicated by pre-eclampsia or lUGR compared to normal pregnant placentae. The concentrations of the cytokines IL-6 and interleukin-1 receptor antagonist (IL-1ra) were significantly higher in patients with pre-eclampsia compared to normal pregnant patients whilst there were no significant differences in the concentrations of tumour necrosis factor alpha (TNFα), IL-8, granulocyte macrophage- colony-stimulating factor (GM-CSF) and IL-1(3. IL-6 induced the expression of E- Selectin and VCAM-2 mRNA and protein on human umbilical vein endothelial cells, which was both time and dose dependent. The presence of increased concentrations of VCAM-1, E-Selectin, IL-6 and IL-1ra may all contribute to the endothelial damage seen in pre-eclampsia and may explain the mechanism underlying leucocyte activation in this disorder. Management of preeclampsia focuses on controlling blood pressure but effective treatment will only come as a result of a clearer understanding of the pathogenesis of the disease.