Vascular Endothelial Growth Factor-A and Aldosterone

Abstract

Abstract-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. (Hypertension. 2013;61:1111-1117.) • Online Data SupplementKey Words: adrenal cell ■ aldosterone ■ aldosterone synthase ■ preeclampsia ■ soluble fms-like tyrosine kinase-1 ■ steroidogenic acute regulatory protein ■ vascular endothelial growth factor

Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy

“…Such a paradox in salt handling in pregnancy underlines the assumption that aldosterone and Na + regulation are (at least partially) uncoupled in pregnancy. Stimulation of aldosterone production by pregnancy‐derived angiogenic signals is well conceivable as a contributor of aldosterone stimulation independent of the RAS 4. The salt retention is extreme during LS conditions in pregnancy, indicating a highly capable mechanism.…”

“…Volume expansion prevails in pregnancy, while tight control by the renin‐angiotensin system (RAS) and consecutive aldosterone production via tubular Na + sensing1 is uncoupled in pregnancy 2, 3, 4. In pregnancy, aldosterone levels are high despite plasma volume expansion and also less responsive to increased Na + intake.…”

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation

“…Obviously, the aldosterone-dependent PlGF stimulation is not challenged in the first trimester in pregnancy. Earlier studies suggest an insufficient aldosterone response in the high aldosterone pregnancy state, either genetically or due to modifying factors (3,9).…”

“…These include, but are not limited to maternal plasma volume expansion, improved fetal conditions and size, placental growth and lower maternal blood pressure (2)(3)(4)(5)(6)(7)(8). We recently described that vascular endothelial growth factor (VEGF) alone and in combination with angiotensin II, directs augmented aldosterone production in pregnancy (9), suggesting a physiological survival benefit.…”

Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus

“…While the relationship between sodium intake and activation of the RAAS is the same in males and females (17, 40 -42, 45, 49, 51, 52), sexual dimorphism must be considered when comparing absolute mineralocorticoid levels between males and females because progesterone is a competitive antagonist of the MR that reaches relevant concentrations for MR occupation during the luteal phase (3). Plasma renin and aldosterone concentrations cycle in parallel to progesterone throughout the normal estrous cycle and pregnancy to maintain normal MR occupancy by aldosterone in aldosterone target cells, thus ensuring fluid, electrolyte and cardiovascular homeostasis (1,30,53). While animal research has tended to favor the use of males because they are thought to be simpler, this bias is not always warranted.…”