Abstract
The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR/LRP) has several ligands including activated alpha 2-macroglobulin, pregnancy zone protein, and very low density lipoproteins enriched with apolipoprotein E. The diversity of ligands suggests a role for the alpha 2MR/LRP in a variety of processes including tissue remodeling and lipoprotein metabolism. We examined alpha 2MR/LRP in placental trophoblasts, invasive cells that also function in lipid transport and cholesterol metabolism. alpha 2MR/LRP protein was localized by immunohistochemistry in the syncytiotrophoblast of term placenta. Cytotrophoblasts did not stain prominently. alpha 2MR/LRP (protein and message) in primary cultures of human trophoblast cells increased as cytotrophoblasts differentiated into syncytiotrophoblast. 8-Bromo-cAMP prevented this increase and suppressed alpha 2MR/LRP expression. The cyclic nucleotide had similar suppressive effects on alpha 2MR/LRP in BeWo choriocarcinoma cells. In contrast, low density lipoprotein receptor gene expression was increased. We conclude that: 1) there is a differentiation-dependent pattern of alpha 2MR/LRP expression in the human trophoblast; 2) cAMP negatively regulates alpha 2MR/LRP; 3) there is an inverse relationship between alpha 2MR/LRP and low density lipoprotein receptor gene expression in trophoblast cells.
Highlights
From the $Departmentof Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and the TBiochemistry Laboratory, American Red Cross Laboratories, Rockville,Maryland 20855
We examined aZMR/LRP inplacental trophoblasts, invasive cells that function in lipid transport and cholesterol metabolisma.ZMR/LRP protein was localizedby immunohistochemistryin the syncytiotrophoblast of termplacenta.Cytotrophoblasts didnot stain prominently. aZMR/LRPinprimaryculturesof humantrophoblast cells increased as cytotrophoblastsdifferentiated into syncytiotrophoblast.8-Bromo-CAMPprevented this increaseandsuppressed aZMR/LRP expression.The cyclic nucleotidehadsimilarsuppressive effects on aZMR/LRPin BeWo choriocarcinomacells
Receptor mRNA in BeWo cterlelasted with 8-Br-CAMP
Summary
With the a2MR/LRP, including activated az-macroglobulin, which binds proteases and several growth factors and cytokines [4], pregnancy zone protein [5], very low density lipoproteins (VLDL) enrichedwith apolipoprotein E [6, 7], and a 39-kDa protein that co-purifies with the azMR/LRP and that has been named receptor-associated protein (RAP) [8,9]. The replicating trophoblast cells (cytotrophoblasts) subsequently differentiate to form post-mitotic multinucleatecells (syncytiotrophoblast)that lie on the surface of the placental chorionic villi [12]. The syncytiotrophoblast is both a transporting epithelium, moving nutrients from the maternalcirculation to thefetal blood, and an endocrine cell, which elaborates steroidalhormones essential for the maintenance of pregnancy.
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