Progesterone inhibits human endothelial cell proliferation through a p53-dependent pathway.

Abstract. Previous studies have shown that progesterone
inhibits endothelial cell proliferation through a
nuclear receptor-mediated mechanism. Here, we
further demonstrate that progesterone at physiologic
levels (5 – 500 nM) dose- and time-dependently inhibited
DNA synthesis of cultured human umbilical
vein endothelial cells (HUVEC). The mRNA and
protein levels of p21, p27, and p53 in HUVEC were
increased by progesterone. The formation of CDK2-
p21 and CDK2-p27 were increased and the CDK2
activity was decreased in the progesterone-treated
HUVEC. The progesterone-inhibited [3H]thymidine
incorporation was completely blocked when the
expressions of p21 and p27 were knocked-down
together. Transfection of HUVEC with dominant
negative p53 cDNA prevented the progesteroneinduced
increases in p21 and p27 promoter activity
and protein level, decreases in thymidine incorporation,
and capillary-like tube formation. Matrigel
angiogenesis assay in mice demonstrated the antiangiogenic
effect of progesterone in vivo. These
findings demonstrate for the first time that progesterone
inhibited endothelial cell proliferation through a
p53-dependent pathway.