Progesterone regulates proliferation of endothelial cells.
The use of steroid hormones in postmenopausal replacement therapy has been associated with prevention of cardiovascular disease. Although the contribution of estradiol to endothelial cell function has been addressed, little information is available on the effect of progestins on this cell type. Here, we provide direct evidence for the presence of functional nuclear progesterone receptor in endothelial cells and demonstrate that physiological levels of progesterone inhibit proliferation through a nuclear receptor-mediated mechanism. The effects of progesterone were blocked by pretreatment with a progesterone receptor antagonist, and progesterone receptor-deficient endothelial cells failed to respond to the hormone. We evaluated the effect of progesterone by analysis of aorta re-endothelialization experiments in wild-type and progesterone receptor knockout mice. The rate of re-endothelialization was significantly decreased in wild-type mice when in the presence of progesterone, whereas there was no difference between control and progesterone-treated progesterone receptor knockout mice. FACS analysis showed that progestins arrest endothelial cell cycle in G1. The lag in cell cycle progression involved reduction in cyclin-dependent kinase activity, as shown by down-regulation in retinoblastoma protein phosphorylation. In addition, treatment of endothelial cells with progestins altered the expression of cyclin E and A in accordance with G1 arrest. These results have important implications to our current knowledge of the effect of steroids on endothelial cell function and to the overall contribution of progesterone to vascular repair.
Vázquez
F
F
Department of Pathology, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Rodríguez-Manzaneque
J C
JC
Lydon
J P
JP
Edwards
D P
DP
O'Malley
B W
BW
Iruela-Arispe
M L
ML
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011374:Progesterone / Q000494:pharmacology*
D011374:Progesterone