Paracrine stimulation of capillary endothelial cell migration by endometrial tissue involves epidermal growth factor and is mediated via up-regulation of the urokinase plasminogen activator receptor

Endometrial angiogenesis is not well studied, but has potential as a model for studies of physiological angiogenesis. Migration as well as proliferati on of vascular endothelial cells are modulated by other endometrial cells. This study analyzes the chemotactic signal released from endometrial tissue in a wound assay using human microvascular endothelial cells. Endometrial tissue explants stimulate migration, and this effect is significantly weake r with explants taken at midcycle than those obtained earlier or later in t he cycle. Migration is inhibited more than 50% by either blocking antibodie s to the urokinase plasminogen activator receptor (uPAR) or enzymatic remov al of uPAR from the cell surface. Also, migration is inhibited more than 50 % by antibodies to epidermal growth factor (EGF), but not by antibodies to vascular endothelial growth factor or basic fibroblast growth factor. The c ombination, of anti-EGF and anti-uPAR antibodies does not further reduce th e response, suggesting that these antibodies target a common pathway. Condi tioned medium from endometrial explants contains EGF, and EGF stimulates th e migration of endothelial cells in a dose-dependent way. This effect is co mpletely blocked by antibodies to uPAR. These data suggest up-regulation of the uPA system by EGF. Conditioned medium from EGF-treated cells contains less uPA than medium from control cells. In contrast, binding of radiolabel ed uPA reveals an increased number of uPA-binding sites in EGF-treated cell s. Increased expression of uPAR potentially increases the activation and as sembly of focal adhesion sites, a prerequisite for cell migration. We concl ude that the endometrial migratory signal has two components. The major par t of the signal is blocked by antibodies to EGF, and the response is mediat ed via upregulation of uPAR in the endothelial cells. The other part of the signal is unknown, and the response does not involve uPAR. Decreased endom etrial chemotactic signal at midcycle is probably related to decreased rele ase of EGF, which is secondary to increased binding to endometrial cell mem branes.