Emerging nonanticoagulant role of low molecular weight heparins on extravillous trophoblast functions and on Heparin Binding Epidermal Growth Factor and Cystein Rich angiogenic inducer 61 expression

This study evaluated the effect of tinzaparin and enoxaparin on extravillous trophoblast (EVTC) invasive properties. The observed beneficial effect of low molecular weight heparins (LMWHs) on EVTC invasiveness and on heparin binding-EGF and Cyr61 expression/secretion suggested a possible biological rationale for the clinical use of LMWHs in placental-mediated pregnancy complications.


Silvia D'Ippolito, M.D., Fiorella Di Nicuolo, Ph.D., Riccardo Marana, M.D., Roberta Castellani, John Stinson, M.D., Chiara Tersigni, M.D., Giovanni Scambia, M.D., Ph.D., Nicoletta Di Simone, M.D., Ph.D.

Vol 98, Issue 4, Pages 1028-1036.e2



To examine the effects of Low Molecular Weight Heparins (LMWHs) on extravillous trophoblast (EVTC) invasiveness and on EVTC expression/secretion of Heparin Binding-EGF (HB-EGF) and Cystein-Rich angiogenic inducer 61 (Cyr61), both involved in the process of EVTC invasion. Furthermore to investigate the intracellular DNA binding activity of Activator Protein (AP)-1.


Experimental study.


Dept Obstetrics Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy.


Cultures of primary EVTC cells isolated from patients with first trimester unexplained recurrent miscarriage.


The effects of LMWHs on EVTC invasiveness was examined by an in vitro matrigel invasion assay. Matrix Metalloprotease-2 activity (MMP-2)by gelatin zimography. HBEGF and Cyr61 expression and secretion were studied by Western Blot analysis and ELISA assay. AP-1 activity was measured through a multiwell colorimetric assay.

Main Outcome Measure(s):

The EVTC invasiveness, the expression/secretion of HBEGF and Cyr61 proteins and the AP-1 DNA binding activity in presence of increasing concentrations of LMWHs were investigated.


Both LMWHs, and primarily tinzaparin, increased EVTC invasiveness, by enhancing the MMP-2 proteolytic activity, and induced the expression/secretion of HB-EGF and Cyr61 in EVTC. This effect was mediated by an increased DNA binding activity of AP-1.


Both LMWHs are able to promote EVTC development being able to stimulate the EVTC invasive properties. Our results may provide a possible biological rationale for the clinical use of LMWH for placental-mediated pregnancy complications unrelated to prothrombotic disorders.

Read the full text at: http://www.fertstert.org/article/S0015-0282(12)00695-4/fulltext

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