MT-MMPs in pre-eclamptic placenta: Relationship to soluble endoglin production

Introduction: Pre-eclampsia is a serious complication of pregnancy, characterized by severe endothelial dysfunction resulting in hypertension, proteinuria and maternal end-organ damage. Soluble endoglin is an anti-angiogenic factor released from placenta that has been linked to severe pre-eclampsia. We recently reported MMP-14 is capable of cleaving endoglin to release soluble endoglin from placenta, however inhibition studies only partially repressed production. To this end we have sought to identify other proteases that mediate endoglin shedding from placenta. MMP-14 is one of six-membrane-type (MT-) MMPs, a sub-family of the MMP superfamily, so named because they are membrane bound. MMP-15 is phylogenetically the closest MMP relative to MMP-14, however its inhibition has no effect on soluble endoglin production from placenta. Methods: Here we aimed to characterize the remaining four MT-MMPs (MMP-16, -17, -24 and -25) in severe early-onset pre-eclamptic placenta and assess their relative contribution to soluble endoglin production. Results: Immunolocalisation studies revealed MMP-16, -24 and -25 were localized to the syncytiotrophoblast, the same site as endoglin, whilst MMP-17 was predominantly localized to fetal vessels and underlying stroma. MMP-17 protein was significantly (p <0.05) up-regulated in pre-eclamptic placentas compared to gestationally matched pre-term controls, whilst MMP-25 mRNA was significantly (p <0.05) down regulated. siRNA knockdown of MMP-16, -17, -24 and -25 in syncytialised BeWo cells did not alter soluble endoglin production in vitro. Conclusion: This is the first study to characterize MT-MMP protein localization in human placenta and indicates that MMP-14 is the only MT-MMP that contributes to soluble endoglin production in pre-eclampsia.