Human Reproduction, Vol 12, 2756-2761, Copyright © 1997 by Oxford University Press
A Lee, LK Christenson, PE Patton, KA Burry and RL Stouffer
Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF)
originating from the follicle or corpus luteum may be a physiological
regulator of ovulation and neovascularization of luteinizing tissue, as
well as a pathological factor in the development of ovarian
hyperstimulation syndrome (OHSS). The objective of this study was to
quantify VEGF production by human luteinized granulosa cells in vitro and
to determine if gonadotrophin stimulates VEGF production directly and/or
indirectly via enhanced synthesis of progesterone. In study 1, luteinized
granulosa cells collected from women undergoing ovarian stimulation for
in-vitro fertilization were cultured in the presence and absence of human
chorionic gonadotrophin (HCG; 100 ng/ml) and/or low density lipoprotein
(LDL; 100 microg protein/ml). In study 2, the progesterone synthesis
inhibitor trilostane (250 ng/ml) and/or a progesterone receptor antagonist
ZK137.316 (3.2 microM) were also added. Medium was harvested on days 1, 3,
5, 7 and 9 of culture and assayed for VEGF and progesterone. Results of
study 1 were divided into two categories based on control concentrations of
VEGF on day 1: 'low producers' (n = 6; <750 pg VEGF/ml) and 'high
producers' (n = 5; >1000 pg VEGF/ml; P < 0.01). VEGF concentrations
in cultures of both low and high producers increased (P < 0.01) from day
1 to maximal values on day 3, then steadily declined through to day 9.
Chronic exposure to LDL or HCG increased (P < 0.05) VEGF concentrations
in cultures of low producers by day 3 and day 5 respectively. In contrast,
LDL did not alter VEGF concentrations in cultures of high producers and HCG
did not increase VEGF concentrations until day 7. Nevertheless, acute
exposure to HCG beginning on day 7 increased (P < 0.05) VEGF
concentrations 3-fold in cultures of low or high producers. In study 2,
trilostane treatment decreased (P < 0.05) progesterone concentrations by
91% on day 1 of culture but had no effect on VEGF concentrations on any
day. ZK137.316 alone or with trilostane did not affect VEGF synthesis.
These results suggest that VEGF production by luteinized granulosa cells is
enhanced by gonadotrophin (HCG) independent of gonadotrophin-stimulated
progesterone synthesis. These data are consistent with the hypothesis that
the exacerbation of OHSS in early pregnancy is mediated by the CG
stimulation of luteal VEGF production.
ARTICLES
Vascular endothelial growth factor production by human luteinized granulosa cells in vitro
Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, USA.
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