PP060. Matrix metalloproteinases-2 and -9 and their inhibitors: A role in the development of pre-eclampsia?

Abstract

Introduction: Pre-eclampsia (PE) is a common and potentially life-threatening condition, affecting 3-10% pregnancies[1]. Placentation has been shown to be deficient in PE and this may be a result of impaired trophoblast invasion [1]. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes which may be important in trophoblast invasion. The activity of MMPs is regulated by tissue inhibitors (TIMPs) and it has been proposed that alterations in MMP/TIMP levels may alter net MMP activity and play a part in both the early and late pathophysiology of pre-eclampsia [2]. Previous studies have largely looked at both active and latent MMP-9 and there is a need for more studies looking specifically at the active forms of these enzymes.

Objectives: The aims of this study were to characterise active MMP-9 expression throughout normal gestation by immunohistochemical localisation, and to compare the levels of MMP-2, -9 (both pro and active) and TIMP-2 in normal and pre-eclamptic term placentae.

Methods: Immunohistochemical localisation of active MMP-9 was carried out on a gestational series of normal placentae from 6-41 weeks' gestation. Quantification of MMP and TIMP levels in term healthy (n=12), pre-eclamptic (n=16) and IUGR (n=12) placental homogenates was done by gelatin-substrate zymography and ELISA. Placentae from IUGR and healthy pregnancies were used as controls to allow us to identify and PE-specific alterations.

Results: Using immunohistochemical localisation, we demonstrated a negative relationship between gestational age and active MMP-9 expression throughout normal gestation (p=0.012). The zymographic and ELISA results showed no significant difference in MMP-2, MMP-9 or TIMP-2 levels in placenta from the healthy, pre-eclamptic and IUGR groups (p>0.05).

Conclusion: To our knowledge, this is the first report using immunohistochemistry to specifically localise the active form of MMP-9 in a gestational series of this size. Our findings demonstrate that there may be high MMP-9 activity during early gestation, which is consistent with a key role for this enzyme in the process of placentation. Thus, it is important to determine if MMP-9 activity is abnormal in PE. In term placentae no difference was found in protein levels of MMPs and TIMPs between control and PE samples; further studies are ongoing to study the MMP and TIMP mRNA expression in these samples.