title: OS067. VEGF, a novel stimulator of aldosterone production.
abstract: BACKGROUND
  Adrenal aldosterone production depends upon capillary integrity. Inadequately explained by increased renin secretion, aldosterone is high in pregnancy, a proangiogenic state. In preeclampsia, low aldosterone levels coincide with disturbed endothelial integrity due to disrupted VEGF signaling.
  
  
  OBJECTIVE
  We hypothesized that the stimulation of adrenal aldosterone production is VEGF-sensitive.
  
  
  METHODS
  We cultured endothelial cells (EC) in the presence and absence of VEGF. The supernatent was transferred to cultured adrenal cells, either the cell line H295R or isolated primary human adrenal cells from zona glomerulosa. aldosterone synthase mRNA and protein expression, aldosterone synthesis was assessed by adding radioactive labeled precursors or measuring aldosterone in the supernatent by Elisa. Cells were cultured either with angiotensin II (Ang II), VEGF or a combination hereof. Adenovirus-based overexpression of the soluble VEGF receptor type 1 (sFlt-1) was used to simulated conditions of preeclampsia in rats and its effect on the adrenocortical vasculature and circulating aldosterone levels.
  
  
  RESULTS
  EC conditioning in the presence of VEGF enhanced aldosterone synthase activity in human adrenocortical cells. VEGF either alone or combined with Ang II increased aldosterone synthase transcription, enzyme availability and aldosterone production in adrenal cells. Neuropilin-1 and VEGF receptor expression differed only for Flt-1 which was present in ECs but not in adrenocortical cells. In contrast to Ang II, VEGF did not upregulate the steroidogenic acute regulatory protein. In line with this observation, Ang II stimulated both aldosterone and cortisol synthesis from progesterone whereas VEGF preferably the former. In rats, overexpression of sFlt-1 which traps VEGF led to adrenocortical capillary rarefaction. Serum aldosterone concentrations inversely correlated with sFlt-1 levels.
  
  
  CONCLUSIONS
  In conclusion, VEGF stimulates aldosterone production indirectly via ECs and directlyin adrenocortical cells a finding explaining the increased aldosterone/renin ratio in normal pregnancy. It is reasonable to assume that the inappropriately low aldosterone availability in preeclampsia is a consequence of the known disturbed VEGF signaling.
authors.affiliation: Nephrology/Hypertension, University of Bern, Bern, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Gennari-Moser
authors.affiliation: Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
authors.forename: E V
authors.initials: EV
authors.lastname: Khankin
authors.affiliation: Urology, University of Bern, Bern, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Escher
authors.affiliation: University of Bern, Bern, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Burkhard
authors.affiliation: Nephrology/Hypertension, University of Bern, Bern, Switzerland.
authors.forename: B M
authors.initials: BM
authors.lastname: Frey
authors.affiliation: Nephrology/Hypertension, University of Bern, Bern, Switzerland.
authors.forename: A S
authors.initials: AS
authors.lastname: Karumanchi
authors.affiliation: University of Bern, Bern, Switzerland.
authors.forename: F J
authors.initials: FJ
authors.lastname: Frey
authors.affiliation: Nephrology/Hypertension, University of Bern, Bern, Switzerland.
authors.forename: M G
authors.initials: MG
authors.lastname: Mohaupt