Low-molecular Weight Heparin Induces In Vitro Trophoblast Invasiveness: Role of Matrix Metalloproteinases and Tissue Inhibitors

• Published in: Placenta (Eastbourne) 2007-04, Vol.28 (4), p.298-304
• Main Authors: Di Simone, N, Di Nicuolo, F, Sanguinetti, M, Ferrazzani, S, D'Alessio, M.C, Castellani, R, Bompiani, A, Caruso, A
• Format: Article
• Language: English
• Subjects: Anticoagulants - pharmacology; Biological and medical sciences; Cell Movement - drug effects; Choriocarcinoma - drug therapy; Choriocarcinoma - enzymology; Choriocarcinoma - pathology; Dose-Response Relationship, Drug; Embryology: invertebrates and vertebrates. Teratology; Fundamental and applied biological sciences. Psychology; Gene Expression; Heparin; Heparin, Low-Molecular-Weight - pharmacology; Internal Medicine; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Metalloproteinase; Neoplasm Invasiveness; Obstetrics and Gynecology; Pregnancy; RNA, Messenger - metabolism; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Trophoblast; Trophoblasts - cytology; Trophoblasts - drug effects; Trophoblasts - enzymology; Tumor Cells, Cultured
• ISSN: 0143-4004; 1532-3102
• DOI: 10.1016/j.placenta.2006.04.001

Abstract 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.