TY - JOUR
T1 - 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.
AU - D'Ippolito, Silvia
AU - Di Nicuolo, Fiorella
AU - Marana, Riccardo
AU - Castellani, Roberta
AU - Stinson, John
AU - Tersigni, Chiara
AU - Scambia, Giovanni
AU - Di Simone, Nicoletta
PY - 2012
Y1 - 2012
N2 - OBJECTIVE:
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 of which are involved in the process of EVTC invasion. Furthermore, to investigate the intracellular DNA binding activity of activator protein (AP)-1.
DESIGN:
Experimental study.
SETTING:
Department of Obstetrics Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy.
PATIENT(S):
Cultures of primary EVTC cells isolated from patients with first trimester unexplained recurrent miscarriage.
INTERVENTION(S):
The effects of LMWHs on EVTC invasiveness were examined by an in vitro matrigel invasion assay. Matrix metalloprotease-2 activity (MMP-2) was examined by gelatin zimography. HB-EGF 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 HB-EGF and Cyr61 proteins, and the AP-1 DNA binding activity in the presence of increasing concentrations of LMWHs were investigated.
RESULT(S):
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.
CONCLUSION(S):
Both LMWHs are able to promote EVTC development because they are 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.
AB - OBJECTIVE:
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 of which are involved in the process of EVTC invasion. Furthermore, to investigate the intracellular DNA binding activity of activator protein (AP)-1.
DESIGN:
Experimental study.
SETTING:
Department of Obstetrics Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy.
PATIENT(S):
Cultures of primary EVTC cells isolated from patients with first trimester unexplained recurrent miscarriage.
INTERVENTION(S):
The effects of LMWHs on EVTC invasiveness were examined by an in vitro matrigel invasion assay. Matrix metalloprotease-2 activity (MMP-2) was examined by gelatin zimography. HB-EGF 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 HB-EGF and Cyr61 proteins, and the AP-1 DNA binding activity in the presence of increasing concentrations of LMWHs were investigated.
RESULT(S):
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.
CONCLUSION(S):
Both LMWHs are able to promote EVTC development because they are 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.
KW - Cyr61
KW - Extravillous trophoblast invasiveness
KW - HB-EGF
KW - enoxaparin
KW - low molecular weight heparins
KW - tinzaparin
KW - Cyr61
KW - Extravillous trophoblast invasiveness
KW - HB-EGF
KW - enoxaparin
KW - low molecular weight heparins
KW - tinzaparin
UR - http://hdl.handle.net/10807/26547
U2 - 10.1016/j.fertnstert.2012.06.042
DO - 10.1016/j.fertnstert.2012.06.042
M3 - Article
SN - 0015-0282
VL - 98
SP - 1028
EP - 1036
JO - Fertility and Sterility
JF - Fertility and Sterility
ER -