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.

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

18 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)1028-1036
Numero di pagine9
RivistaFertility and Sterility
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • Cyr61
  • Eparine a basso peso molecolare
  • Extravillous trophoblast invasiveness
  • HB-EGF
  • INVASIVITà DEL TROFOBLASTO ESTRAVILLOSO
  • enoxaparin
  • enoxaparina
  • low molecular weight heparins
  • tinzaparin
  • tinzaparina

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