Pro-opiomelanocortin (
POMC) is the precursor of several
neuropeptides, such as
corticotropin (
ACTH),
alpha-melanocyte-stimulating hormone (
MSH), and the endogenous
opioid,
beta-endorphin (EP).
ACTH-dependent
Cushing's syndrome is characterized by
ACTH overproduction and is associated with an increased risk of
cardiovascular disease. Endothelial dysfunction has been recognized as an early marker of
cardiovascular disease. However, the mechanism underlying endothelial dysfunction by
ACTH overexpression in Cushing's patients remains elusive. Endothelial cells, the primary cells producing
endothelin (ET)-1, are both the source and target of
POMC-derived
peptides. In the present study, we generated adenovirus vectors (Ad) encoding
POMC (Ad-
POMC) and
green fluorescent protein (GFP; Ad-GFP) to investigate whether
POMC gene transfer altered the ET-1 homeostasis and angiogenic functions in human EA.hy926 endothelial cells. Via adenovirus gene delivery, the
POMC-transduced EA.hy926 cells released significantly elevated
ACTH and beta-EP levels (P < 0.001). In addition,
POMC gene delivery significantly decreased the ET-1 release (P < 0.001) without affecting the ET-1
messenger RNA (
mRNA) level. Despite no effect on the secretion of
matrix metalloproteinases (
MMPs) and cell proliferation,
POMC gene delivery significantly inhibited the migration (P < 0.01) and tube-forming capability (P < 0.01) of endothelial cells. Moreover, the
POMC-induced inhibition of tube formation could be partially reversed by adding exogenous ET-1 (P < 0.05). In summary, the attenuated ET-1 release and angiogenic processes by
POMC overexpression may contribute to endothelial dysfunction, thereby providing a link between
Cushing's syndrome and
cardiovascular diseases.