title: MMP-14 is expressed in preeclamptic placentas and mediates release of soluble endoglin.
abstract: Soluble endoglin is an anti-angiogenic protein that is released from the placenta and contributes to both maternal endothelial dysfunction and the clinical features of severe preeclampsia. The mechanism through which soluble endoglin is released from the placenta is currently unknown; however, recent work in colorectal cancer identified matrix metalloproteinase 14 (MMP-14) as the cleavage protease of endoglin. To determine whether this is also the mechanism responsible for soluble endoglin release in preeclampsia, we investigated the expression of MMP-14 within the placenta and the effects of its inhibition on soluble endoglin release. Placentas were obtained from severe, early onset preeclamptic pregnancies (n = 8) and gestationally matched preterm controls (n = 8). MMP-14 was predominately localized to the syncytiotrophoblast. Results from a proximity ligation assay showed protein interactions between endogenous MMP-14 and endoglin within the preeclamptic placenta. To demonstrate that this interaction produces soluble endoglin, we treated trophoblastic BeWo cells with either a broad-spectrum MMP inhibitor (GM6001) or MMP-14 siRNA. Both treatments produced a decrease in soluble endoglin (P ≤ 0.05). Treatment of mice bearing BeWo xenografts with GM6001 decreased circulating soluble endoglin levels in mouse serum (P ≤ 0.05). These findings indicate that MMP-14 is the likely cleavage protease of endoglin in the setting of preeclampsia. This approach provides a novel method for the development of potential therapeutics to reduce circulating soluble endoglin and ameliorate the clinical features of severe preeclampsia.
authors.affiliation: Translational Obstetrics Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia; Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia.
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
authors.affiliation: Translational Obstetrics Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia; Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia.
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Palmer
authors.affiliation: Translational Obstetrics Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia; Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Whitehead
authors.affiliation: Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Williams
authors.affiliation: Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia.
authors.forename: Martha
authors.initials: M
authors.lastname: Lappas
authors.affiliation: Translational Obstetrics Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia; Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia. Electronic address: stong@unimelb.edu.au.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D000071063:Endoglin; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism* / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D011225:Pre-Eclampsia / Q000209:etiology* / Q000378:metabolism; D011247:Pregnancy; D011480:Protease Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D004151:Dipeptides; C064206:ENG protein, human; D000071063:Endoglin; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D053511:Matrix Metalloproteinase 14