HUMAN ENDOTHELIAL-CELL MIGRATION IS STIMULATED BY UROKINASE PLASMINOGEN ACTIVATOR-PLASMINOGEN ACTIVATOR INHIBITOR-1 COMPLEX RELEASED FROM ENDOMETRIAL STROMAL CELLS STIMULATED WITH TRANSFORMING-GROWTH-FACTOR BETA-1 - POSSIBLE MECHANISM FOR PARACRINE STIMULATION OF ENDOMETRIAL ANGIOGENESIS

Human endometrial stromal cell cultures, stimulated for two days with recombinant transforming growth factor beta 1 (TGF beta 1; 10 ng/ml), contained conditioned medium concentrations of urokinase plasminogen a ctivator (uPA), plasminogen activator inhibitor 1 (PAI1), and uPA:PAI1 complex. Since a number of cellular effects have been reported to fol low a binding of enzymatically inactive uPA to the receptor in differe nt cell types, we studied the influence of uPA:PAI1 complex on human u mbilical vein endothelial cells (HUVEC) and human microvascular endoth elial cells (HMEC-1). Increasing concentrations of uPA:PAI1 complex as well as free uPA resulted in a dose-dependent stimulation of endothel ial cell migration. Stimulation by the complex was of the same magnitu de as that of free uPA on a molar basis and reached its maximum at 1 n M in both cell types. PAI1 by itself, however, had no effect on cell m igration. The migratory response to both uPA and the uPA:PAI1 complex was inhibited by antibody adhesion to the cell surface receptor for uP A. In addition, we found that TGF beta 1 had a direct stimulatory effe ct on migration in both HUVEC and HMEC-1. This response did not, howev er, involve the binding of uPA to the uPA receptor. Since TGF beta s a re expressed in endometrial tissue and reportedly stimulate angiogenes is in other tissues in vivo, though not endothelial cell proliferation in vitro, they may engage in the regeneration of endometrial vasculat ure indirectly via perivascular cells. We found that the uPA:PAI1 comp lex, when released from endometrial stromal cells in response to TGF b eta 1, stimulated endothelial cell migration. This suggests a possible mechanism for paracrine stimulation of endometrial angiogenesis.