Placental expression of matrix metalloproteinases MMP-2 and MMP-9 in pregnancy: the use of villous explants and high altitude pregnancy studies to explore the role of oxygen in the pathogenesis of pre-eclampsia

Marks, Leah Kathryn (2004) Placental expression of matrix metalloproteinases MMP-2 and MMP-9 in pregnancy: the use of villous explants and high altitude pregnancy studies to explore the role of oxygen in the pathogenesis of pre-eclampsia. PhD thesis, University of Glasgow.

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The first aim of this study was to investigate levels of MMP-2, MMP-9, TIMP-1, TIMP-2 and HIF-1? in placentae throughout pregnancy using various techniques. The study used immunohistochemistry to detect and quantify MMP-2 and MMP 9 expression in placentae from 7-19 and at 40 weeks of gestation. A reduction was found in extravillous trophoblast (EVT) expression of both MMPs as pregnancy progressed. In contrast endothelial expression of both MMPs increased. MMP-2 expression in villous CTB (vCTB) was highest in early pregnancy but decreased with gestation. MMP-9 expression in vCTB was very low throughout pregnancy. Zymography studies revealed a significant decrease in pro-MMP-2 but not pro-MMP-9 activity through gestation although the latter did decrease during the first trimester. The results of the study suggest a role for MMP-2 and MMP-9 not only in early placental development but also in vascular remodelling in the later stages of gestation. Moreover it also suggests that the role of MMP-2, often regarded as less important than MMP-9 in placental development, warrants further study. Immunohistochemical studies on the same placentae showed that TIMP-1 expression in muscle surrounding the villous endothelium and in the villous stroma increased with gestation while vCTB expression did not alter and EVT expression increased during the second trimester. TIMP-2 staining in vCTB decreased with gestation while staining on endothelium, muscle and stroma increased. EVT expression of TIMP-2 was negatively correlated with gestation. Thus TIMP-2 appeared to have a high degree of co-distribution with MMP-2 both spatially and temporally. HIF-1alpha staining on vCTB and EVT decreased with gestation while expression on the endothelium increased. These results suggest both paracrine and autocrine regulation of MMPs may occur early in pregnancy. Furthermore TIMPs and HIF-1alpha may have a role in regulating the processes in which MMPs are involved in later on in pregnancy. Pregnant women living at high altitude are exposed to chronic hypoxia throughout gestation. It has been reported that high altitude pregnancies show physiology intermediate between normal pregnancy and pre-eclampsia and thus may provide a useful in vivo model of the disease. This study compared MMP-9 and MMP-2 expression in placentae from high, moderate and low altitude. Endothelial expression of MMP-9 was lower at high altitude than low altitude while MMP-9 expression in the villous stroma was higher. This may implicate MMP-9 in adaptive responses to hypoxia and villous remodelling in high altitude placentae. There were no differences in MMP-2 expression between high and low altitude placentae supporting previous studies, which have reported that MMP-2 expression may not be subject to regulation by oxygen. Maternal serum markers of endothelial cell activation were measured throughout pregnancy at high and moderate altitude. It was hypothesised that since circulating VCAM-1 and E-Selectin are increased in pre-eclampsia, they might also be elevated in high altitude pregnancy. This hypothesis was not supported and another marker of endothelial activation, ICAM-1, was not found to be increased either. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Obstetrics.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Lyall, Prof. Fiona
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-71090
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 12 Jul 2021 15:04
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