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ToxSci Advance Access published online on March 2, 2006
Toxicological Sciences, 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
Received September 20, 2005
Accepted February 22, 2006

Reproductive and Developmental Toxicology

Macaque Trophoblast Migration Towards Rantes is Inhibited by Cigarette Smoke-Conditioned Medium

Twanda L. Thirkill 1, Hemamalini Vedagiri 1, and Gordon C. Douglas 1 *

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

* To whom correspondence should be addressed.
Gordon C. Douglas, E-mail: gcdouglas{at}ucdavis.edu


  Abstract

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 towards RANTES. 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. Cell migration was quantified using migration chambers. CCR5 and G protein receptor kinase 2 (GRK2) expression were measured by immunofluorescence microscopy and Western blotting. cAMP levels were measured by ELISA. Trophoblast migration towards RANTES was reduced when cells were incubated in cigarette smoke-conditioned medium. 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 cigarette smoke-conditioned medium. 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.

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