Mol. Hum. Reprod. Advance Access published online on February 27, 2008
Molecular Human Reproduction, doi:10.1093/molehr/gan010
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Progestogens Regulate Endothelial Actin Cytoskeleton and Cell Movement via the Actin-Binding Protein Moesin
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa 56100, Italy
Corresponding author: Tommaso Simoncini, M.D., Ph.D., Tel: +39.050.553412; Fax: +39.050.553410, E-mail: t.simoncini{at}obgyn.med.unipi.it
The endothelial effects of progestogens are poorly investigated. Actin remodeling and cell movement are fundamental for endothelial function and are controlled by the actin-binding protein moesin. In this work we studied the effects of progesterone and medroxyprogesterone acetate (MPA) on actin remodeling, moesin activation and cell movement in human endothelial cells. Our findings show that progesterone and MPA trigger a rapid endothelial actin rearrangement, with the formation of cortical actin complexes, pseudopodia and membrane ruffles. Both progestogens trigger a rapid progesterone receptor (PR)-dependent moesin activation via a nongenomic signalling cascade involving G proteins, the small GTPase RhoA and the Rho-associated kinase (ROCK-2). In addition, MPA signalling also requires the recruitment of phosphatidylinositol-3 kinase (PI3K). Both progestogens enhance endothelial cell migration, which is prevented by moesin silencing or by blockade of PR, G proteins, PI3K, mitogen-activated protein kinases or ROCK-2. Progesterone and MPA potentiate 17β-estradiol (E2) induced-moesin activation. However, they partially reduce cell migration induced by E2. In conclusion, progesterone and MPA regulate endothelial cell movement by rapidly signalling to the actin-binding protein moesin and to the actin cytoskeleton. These findings provide new information on the biological actions of progestins on human endothelial cells that are relevant for vascular function.
Key Words: progesterone/medroxyprogesterone acetate/vascular endothelial cells/moesin/cell movement
* These two authors contributed equally to this work
Disclosure statement: The authors of this manuscript have nothing to declare.
Authors’ roles: All authors meet the qualification of MHR. Xiao-Dong Fu and Marina Flamini designed and carried out the experiments, analysed the data, drafted and revised the manuscript; Angel Matias Sanchez, Lorenzo Goglia and Maria Silvia Giretti carried out some experiments; Andrea R. Genazzani, raised funds for the project, discussed the project and the results, reviewed the manuscript; Tommaso Simoncini, raised funds for the project, designed the experiments, analysed the data, drafted and revised the manuscript.
Submitted on December 13, 2007; resubmitted on February 9, 2008; accepted on February 22, 2008.