Aldosterone levels are markedly elevated during normal pregnancy but fall even though volume contracts when
preeclampsia occurs. The level of
aldosterone in either condition cannot be explained solely by the activity of the
renin-
angiotensin II system. In normal gestation,
vascular endothelial growth factor (
VEGF) is thought to maintain vascular health, but its role in adrenal
hormone production is unknown. We hypothesized that the role of
VEGF in the adrenal gland is to maintain vascular health and regulate
aldosterone production. Here, we demonstrate that supernatant of endothelial cells grown in the presence of
VEGF enhanced
aldosterone synthase activity in human adrenocortical cells.
VEGF either alone or combined with
angiotensin II increased
aldosterone production in adrenal cells. These data suggest that endothelial cell-dependent and independent activation of
aldosterone is regulated by
VEGF. In contrast to
angiotensin II,
VEGF did not upregulate the
steroidogenic acute regulatory protein. Consistent with this observation,
angiotensin II stimulated both
aldosterone and
cortisol synthesis from
progesterone, whereas
VEGF stimulated selectively
aldosterone production. In rats, overexpression of soluble fms-like
tyrosine kinase-1, an endogenous
VEGF inhibitor, led to adrenocortical
capillary rarefaction and fall in
aldosterone concentrations that correlated inversely with soluble fms-like
tyrosine kinase-1 levels. These findings may explain why
aldosterone increases so markedly during normal gestation and why
preeclampsia, a condition characterized by high soluble fms-like
tyrosine kinase-1, is associated with inappropriately low
aldosterone levels in spite of relatively lower plasma volumes.