The use of steroid hormones in postmenopausal replacement therapy has been
associated with prevention of cardiovascular disease. Although the contribu
tion of estradiol to endothelial cell function has been addressed, little i
nformation is available on the effect of progestins on this cell type. Here
, we provide direct evidence for the presence of functional nuclear progest
erone receptor in endothelial cells and demonstrate that physiological leve
ls of progesterone inhibit proliferation through a nuclear receptor-mediate
d mechanism. The effects of progesterone were blocked by pretreatment with
a progesterone receptor antagonist, and progesterone receptor-deficient end
othelial cells failed to respond to the hormone. We evaluated the effect of
progesterone by analysis of aorta re-endothelialization experiments in wil
d-type and progesterone receptor knockout mice. The rate of re-endotheliali
zation was significantly decreased in wild-type mice when in the presence o
f progesterone, whereas there was no difference between control and progest
erone-treated progesterone receptor knockout mice. FACS analysis showed tha
t progestins arrest endothelial cell cycle in G(1). The lag in cell cycle p
rogression 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 c
yclin E and A in accordance with G(1) arrest. These results have important
implications to our current knowledge of the effect of steroids on endothel
ial cell function and to the overall contribution of progesterone to vascul
ar repair.