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ToxSci Advance Access originally published online on March 2, 2006
Toxicological Sciences 2006 91(2):557-567; doi:10.1093/toxsci/kfj147
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Macaque Trophoblast Migration toward RANTES Is Inhibited by Cigarette Smoke–Conditioned Medium

Twanda L. Thirkill, Hemamalini Vedagiri and Gordon C. Douglas1

Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, Davis, California 95616

Received September 30, 2005; accepted February 22, 2006

Trophoblast migration within the endometrium and uterine vasculature is essential for normal placental and fetal development. We previously demonstrated that macaque trophoblasts express the chemokine receptor CCR5 and that this receptor mediates trophoblast migration toward RANTES (regulated upon activation normal T-cell expressed and secreted). In the present paper we have used primary cultures of early gestation macaque trophoblasts to test the hypothesis that tobacco smoke inhibits trophoblast migration as the result of dysregulation of the RANTES/CCR5 chemotactic axis. Early gestation macaque trophoblasts were incubated in the absence or presence of cigarette smoke–conditioned medium (CSM). Cell migration was quantified using migration chambers. CCR5 and G protein receptor kinase 2 (GRK2) expression was measured by immunofluorescence microscopy and Western blotting. cAMP levels were measured by enzyme-linked immunosorbent assay. Trophoblast migration toward RANTES was reduced when cells were incubated in CSM. Trophoblasts also showed reduced expression of CCR5, increased levels of cAMP, and increased expression of GRK2. Finally, the secretion of RANTES by uterine endothelial cells was reduced by exposing the cells to CSM. These results support the idea that cigarette smoke constituents inhibit directional trophoblast migration by causing increased desensitization of trophoblast CCR5 and inhibiting the secretion of RANTES by endothelial cells.

Key Words: chemokine; CCR5; G protein receptor kinase 2; endothelium; placenta; invasion.


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