Low-molecular weight heparin induces in vitro trophoblast invasiveness: role of matrix metalloproteinases and tissue inhibitors.
Heparin is used widely for the prevention of pregnancy loss in pregnant women with thrombophilia. However, it is still unknown if heparin may be able to affect trophoblast functions. Therefore, we investigated the hypothesis that low-molecular weight heparin (LMWH) might regulate in vitro trophoblast invasiveness and placental production of matrix metalloproteinases (MMPs) and tissue inhibitors (TIMPs). In the first-trimester placental tissue, the MMP-9 expression was observed in both villous and extravillous cytotrophoblast cells, and MMP-2 mainly in villous cytotrophoblast. In human choriocarcinoma cells (JAR), MMP-2 was the dominant form. Heparin significantly enhanced both pro-MMPs and the active forms, and increased Matrigel invasiveness of extravillous trophoblast and choriocarcinoma cells. In choriocarcinoma cells the heparin effect was also indirect, inducing a significant decrease in TIMP-1 and TIMP-2 protein expressions and mRNAs. The present data suggest that the increase in trophoblast invasion by heparin is due to a specific protein playing a role in placental invasion. These observations may help in understanding the effects of heparin treatment during pregnancy.
Di Simone
N
N
Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Largo Gemelli 8, 00168 Rome, Italy. nicoletta.disimone@virgilio.it
Di Nicuolo
F
F
Sanguinetti
M
M
Ferrazzani
S
S
D'Alessio
M C
MC
Castellani
R
R
Bompiani
A
A
Caruso
A
A
D000925:Anticoagulants / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002822:Choriocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D014407:Tumor Cells, Cultured
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9