Abstract
Extravillous trophoblast (EVT) invasion is an essential component of human placentation. Poor EVT invasion is associated with obstetrical complications including preeclampsia. Integration of cues from the extracellular environment is required for directional EVT invasion, but how EVTs coordinate responses to these cues is not well understood. Syndecan-4 (SDC4) is a transmembrane heparan sulfate proteoglycan that binds to, and modulates the activity of, many extracellular proteins implicated in placental development. Therefore, we determined the functional importance of SDC4 for EVT invasion. We found that SDC4 is expressed by a first trimester EVT line (HTR8), and in EVTs in placenta throughout pregnancy, with higher expression during early pregnancy than at term. Higher expression was also observed in placentas from preeclampsia compared to normotensive pregnancies. SDC4-deficient HTR8 EVTs exhibited reduced migration and Matrigel-based invasion, both under basal conditions and following exposure to basic fibroblast growth factor and heparin-binding epidermal growth factor. SDC4-deficient HTR8 EVTs also showed reduced protein kinase C-alpha (PKCα) and AKT phosphorylation. SDC4 directly bound to activated PKCα in EVTs, and inhibition of PKCα decreased EVT invasion and migration. Our findings reveal an essential role of SDC4 as a regulator of EVT motility, in part through coordination of PKCα activation.
Highlights
Extravillous trophoblast (EVT) invasion is an essential feature of human placentation
We found that EVT motility is dependent on the presence of Heparan sulfate proteoglycans (HSPGs)
We discovered that SDC4 is a major HSPG expressed by EVTs
Summary
Extravillous trophoblast (EVT) invasion is an essential feature of human placentation. The EVT occlusions gradually dissipate, and cells progressively displace the endothelium, internal elastic lamina, and smooth muscle layers surrounding the spiral arteries This process results in transformation of spiral arteries into dilated, flaccid conduits capable of delivering a large and consistent supply of maternal blood to the placenta for the remainder of pregnancy[1]. What is not well recognized is how EVTs integrate these distinct extracellular cues to activate intracellular signaling pathways, thereby facilitating tightly controlled migration during early placental development. Given the known importance of SDC4 for focal adhesion turnover, cytoskeletal organization, and cell migration, and high expression of SDC4 in EVTs, we postulated that SDC4-PKCα signaling promotes EVT invasion. We show that SDC4 is dynamically regulated in placenta throughout pregnancy, and that aberrant placental expression of SDC4 is evident in early-onset preeclampsia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
