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Involvement of Membrane-Type Matrix Metalloproteinases (MT-MMPs) in Capillary Tube Formation by Human Endometrial Microvascular Endothelial Cells: Role of MT3-MMP

Department of Biomedical Research (M.P., K.K., P.K., C.F., R.H., J.M.G., A.M.-S., P.H.A.Q., V.W.M.v.H.), Gaubius Laboratory TNO Prevention and Health, 2301 CE, Leiden, The Netherlands; Department of Gynecology and Reproductive Medicine (M.P., K.K., F.M.H.), Leiden University Medical Center, 2300 RC, Leiden, The Netherlands; and Department of Physiology (V.W.M.v.H.), Institute for Cardiovascular Research, VU University Medical Center, 1081 BT, Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: V. W. M. van Hinsbergh, Ph.D., Gaubius Laboratory TNO-PG, Zernikedreef 9, 2333 CK Leiden, The Netherlands. E-mail: v.vanhinsbergh{at}vumc.nl.

In the endometrium, angiogenesis is a physiological process, whereas in most adult tissues neovascularization is initiated only during tissue repair or pathological conditions. Pericellular proteolysis plays an important role in angiogenesis being required for endothelial cell migration, invasion, and tube formation. We studied the expression of proteases by human endometrial microvascular endothelial cells (hEMVECs) and their involvement in the formation of capillary tubes and compared these requirements with those of foreskin MVECs (hFMVECs). Inhibition of urokinase and matrix metalloproteinase (MMP) both reduced tube formation in a fibrin or fibrin/collagen matrix. hEMVECs expressed various MMP mRNAs and proteins; in particular MMP-1, MMP-2, and membrane-type (MT)1-, MT3-, and MT4-MMPs. MT3- and MT4-MMP mRNA expressions were significantly higher in hEMVECs than in hFMVECs. Other MT-MMP mRNAs and MMP-9 were hardly detectable. Immunohistochemistry confirmed the presence of MT3-MMP in endothelial cells of endometrial tissue. Overexpression of tissue inhibitor of MMP (TIMP)-1 or TIMP-3 by adenoviral transduction of hEMVECs reduced tube formation to the same extent, whereas only TIMP-3 was able to inhibit tube formation by hFMVECs. Tube formation by hEMVECs was partly inhibited by the presence of anti-MT3-MMP IgG. Thus, in contrast to tube formation by hFMVECs, which largely depends on MT1-MMP, capillary-like tube formation by hEMVECs is, at least in part, regulated by MT3-MMP.

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