Estradiol induces endothelial cell migration and proliferation through estrogen receptor-enhanced RhoA/ROCK pathway.
Migration and proliferation of endothelial cells are involved in re-endothelialization and angiogenesis, two important cardiovascular processes that are increased in response to estrogens. RhoA, a small GTPase which controls multiple cellular processes, is involved in the control of cell migration and proliferation. Our aim was to study the role of RhoA on estradiol-induced migration and proliferation and its dependence on estrogen receptors activity. Human umbilical vein endothelial cells were stimulated with estradiol, in the presence or absence of ICI 182780 (estrogen receptors antagonist) and Y-27632 (Rho kinase inhibitor). Estradiol increased Rho GEF-1 gene expression and RhoA (gene and protein expression and activity) in an estrogen receptor-dependent manner. Cell migration, stress fiber formation and cell proliferation were increased in response to estradiol and were also dependent on the estrogen receptors and RhoA activation. Estradiol decreased p27 levels, and significantly raised the expression of cyclins and CDK. These effects were counteracted by the use of either ICI 182780 or Y-27632. In conclusion, estradiol enhances the RhoA/ROCK pathway and increases cell cycle-related protein expression by acting through estrogen receptors. This results in an enhanced migration and proliferation of endothelial cells.
Oviedo
Pilar J
PJ
Research Foundation, Hospital Clínico Universitario, Valencia, Spain.
Sobrino
Agua
A
Laguna-Fernandez
Andrés
A
Novella
Susana
S
Tarín
Juan J
JJ
García-Pérez
Miguel-Angel
MA
Sanchís
Juan
J
Cano
Antonio
A
Hermenegildo
Carlos
C
D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D057075:Enzyme Assays; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D014470:Umbilical Cord / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D011960:Receptors, Estrogen; D004958:Estradiol; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein