title: 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.
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.
  
  
  METHODS
  Experimental study.
  
  
  METHODS
  Department of Obstetrics Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy.
  
  
  METHODS
  Cultures of primary EVTC cells isolated from patients with first trimester unexplained recurrent miscarriage.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Silvia
authors: S
authors: D'Ippolito
authors: Fiorella
authors: F
authors: Di Nicuolo
authors: Riccardo
authors: R
authors: Marana
authors: Roberta
authors: R
authors: Castellani
authors: John
authors: J
authors: Stinson
authors: Chiara
authors: C
authors: Tersigni
authors: Giovanni
authors: G
authors: Scambia
authors: Nicoletta
authors: N
authors: Di Simone
mesh_terms: D000026:Abortion, Habitual / Q000188:drug therapy* / Q000473:pathology; D000925:Anticoagulants / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D017984:Enoxaparin / Q000494:pharmacology; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000187:drug effects; D011247:Pregnancy; D013927:Thrombosis / Q000188:drug therapy; D000078222:Tinzaparin; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D017984:Enoxaparin; D005343:Fibrinolytic Agents; C587883:HBEGF protein, human; D006495:Heparin, Low-Molecular-Weight; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D018808:Transcription Factor AP-1; D000078222:Tinzaparin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2