The establishment of an adequate uteroplacental vasculature is vital for normal growth and development of the fetus. Trophoblasts play a major role in the development of this vasculature by migrating through endometrium and remodeling the maternal uterine spiral arteries. This process, termed placentation, leads to effacement of the endothelium and smooth muscle of these vessels and results in the formation of the uteroplacental arteries, which lack smooth muscle and are lined by fibrinoid material and endovascular trophoblast. These vessels deliver maternal blood to the placental intervillous spaces at a rate that approaches 800 ml per minute at term. The factors controlling the invasion and remodeling of the uterus by trophoblasts are not well understood. Several studies suggest that the regulated production of proteases by trophoblasts are involved in this process. The importance of the plasminogen activator (PA) system in placentation is supported by the observations that invading trophoblasts produce urokinase (uPA) and plasminogen activator inhibitors (PAIs). Our previous studies have demonstrated that trophoblasts also express receptors for urokinase (uPAR). These receptors play a central role in cellular migration by focalizing PA activity to discrete sites on the cell surface. The activation of cell-bound plasminogen at these sites initiates a proteolytic cascade leading to direct digestion of extracellular matrix proteins by plasmin, as well as activation of procollagenases. However, the importance of uPAR in the placetation process, as well as the factors controlling trophoblast uPAR expression have not been studied. We propose that regulated expression of uPAR by trophoblasts plays a critical role in placentation, and that decreased expression of these receptors contributes to the pathogenesis of preeclampsia, which is characterized by shallow uterine invasion by trophoblasts, with resultant insufficient remodeling of the spiral arteries. Receptor-bound uPA on invading cells is inhibited by PAI-1 within the extracellular matrix, leading to the formation of uPAR-bound uPA:PAI-1 complexes. To ensure continued expression of PA activity on the cell surface, these proteolytically-inactive complexes must be cleared from the receptor. Recently, the role of the alpha2-macroglobulin receptor (alpha2MR) in the clearance of these complexes has been demonstrated. However, neither the mechanisms by which this process occurs nor the role of the alpha2MR in facilitating cellular invasion have been established. The potential importance of this receptor in mediating trophoblast invasion is, however, supported by the recent observation that embryos with homozygous disruptions in the alpha2MR gene are unable to implant in the uterus. We propose to study in detail the clearance of uPA:PAI-1 complexes bound to trophoblast uPAR, and to determine the role of alpha2MR in this process.
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