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Prostaglandin E₂-Mediated Migration of Human Trophoblast Requires RAC1 and CDC42¹

Departments of Anatomy and Cell Biology³ and Pathology,⁴ Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1

ABSTRACT

The invasion of maternal decidua and uterine spiral arteries by a trophoblast subpopulation called extravillous trophoblast (EVT) is essential for the establishment of a normal placenta and an adequate blood flow toward the fetus. Derangements in these processes underlie pregnancy-related diseases like preeclampsia and intrauterine growth restriction. Many growth factors, growth factor binding proteins, and extracellular matrix components can positively or negatively regulate the proliferation, migration, and/or invasiveness of these EVT cells. RHO GTPases, including RHOA, RAC1, and CDC42, are ubiquitous proteins that control cytoskeletal changes by forming stress fibers and projecting lamellipodia and filopodia during cellular migration. We had previously shown that prostaglandin (PG) E₂ produced in abundance by the decidua promotes the migration of first-trimester human EVTs by increasing the intracellular concentration of calcium and activating calpain. Using our well-characterized immortalized EVT cell line, HTR-8/SVneo, as well as villus explants from first-trimester placentae, this study examined the role of RHO GTPases RAC1 and CDC42 in PGE₂-mediated migratory responses of these cells. Though a RAC1 inhibitor, NSC23766 as well as RAC1 knockdown by siRNA decreased the migration of HTR-8/SVneo cells in a Transwell migration assay, this inhibition could not be restored by PGE₂ or 17-phenyl trinor PGE₂ (PGE receptor PTGER1 agonist) or PGE₁ Alcohol (PGE receptor PTGER4 agonist). Similar results were noted for EVT cell spreading in villus explants. Furthermore, CDC42 silencing using siRNA inhibited PGE₂-induced migration of HTR-8/SVneo cells. Finally, the treatment of EVT cells with PGE₂, PTGER1 agonist, or PTGER4 agonist activated RAC1 and CDC42 at 10 min, suggesting that RAC1 and CDC42 play an essential role in PGE₂-mediated migration of human EVTs.

mechanisms of hormone action, placenta, pregnancy, signal transduction

¹Supported by grant MOP 68997 (to C.C.) and grant MOP 69091 (to P.K.L.) of the Canadian Institutes of Health Research. C.N. is the recipient of a CIHR/STP scholarship in cancer research at UWO.

Correspondence: ²Chandan Chakraborty, Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada. FAX: 519 661 3370; e-mail: cchakrab{at}uwo.ca