IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Role of Vascular Endothelial Cell Growth Factor (VEGF) and Angiopoietins (ANGPTs) in Ovarian Hyperstimulation Syndrome (OHSS).
Autor/es:
DE ZUÑIGA IGNACIO; SCOTTI LEOPOLDINA; ABRAMOVICH DALHIA; COLACI D; HORTON MARCOS; BISIOLI C; TESONE MARTA; PARBORELL FERNANDA
Reunión:
Congreso; 27th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE); 2011
Resumen:
Introduction: Moderate to severe OHSS has been calculated to occur
in 0.2% to 2% of all ovarian stimulation cycles. Risk factors include low body weight, high
follicle count, polycystic ovarian syndrome, previous OHSS and elevated serum
estradiol. VEGF is clearly implicated in the pathogenesis of
OHSS, and it seems to be the principal mediator of the action of hCG. In women
who develop OHSS, VEGF is expressed and produced by granulosa-lutein cells, is
released into the follicular fluid in response to hCG, and in turn, inducing
capillary permeability. The ANGPTs/Tie-2 system acts in concert with VEGF.
ANGPT-1 is necessary to stabilize blood vessels and ANGPT2 acts as natural
antagonist for ANGPT1. The balance between the ANGPT1/ANGPT2 ratio and VEGF
expression is important for angiogenesis in the ovary. However, up to now, the
possible involvement of ANGPTs in OHSS is unknown. Our objectives were to
analyze: 1) the effect of inhibition of VEGF in a rat model of OHSS in the
follicular and luteal development and 2) possible ANGPTs involvement in this
model and in patients undergoing ART with high probability of developing OHSS.
Material and methods: Group OHSS (hyperstimulated immature Sprague Dawley
rats) received excessive doses of pregnant mare serum gonadotropin (PMSG, 50
UI/day) injected for 4 consecutive days (from the 21th day to 24th of life),
followed by human chorionic gonadotropin (hCG, 25 UI, 25th day of life). Group
OHSS+TRAP (TRAP-treated hyperestimulated immature rats) received the same doses
of gonadotropins than in group OHSS and, in turn, received 1 ug Trap (recombinant
mouse-soluble VEGF receptor 1/Fc Chimera) in 5 ul of PBS with 0.1% BSA under
the ovarian bursa in the same day of hCG. Rats were sacrificed 48 hs post hCG. Histological
features of sectioned ovaries were assessed in hematoxilin and eosin stained
slides. Corpora lutea (CLs) were isolated by microdissection under the
microscope for western blot. In addition, the levels of ANGPT1 and Tie-2 were
measured in follicular fluid (FF) of women controls and OHSS by ELISA assay.
Results: In the OHSS group, TRAP increased the number of atretic follicles (OHSS:
0.39 ± 0.25 vs OHSS+TRAP: 9.18 ± 1.39, %FAtr/ovario; p<0.001), decreased the
number of CLs (OHSS: 72.10 ± 4.33 vs OHSS+TRAP: 55.26 ± 3.85, %CL/ovario;
p<0.05) and cysts (OHSS: 7.36 ± 0.66 vs OHSS + TRAP: 3.64 ± 1.29, %Q/ovario;
p<0.01). In addition, TRAP decreased the ovarian weight in OHSS group
respect to the OHSS group without treatment (OHSS: 0.22 ± 0.01 vs OHSS+TRAP:
0.19 ± 0.01, g.; p<0.05). By western blot, the ratio ANGPT1/ANGPT2 increased
(Control: 0.22 ± 0.04 vs OHSS: 0.42 ± 0.07, arbitrary units; p<0.05) and the
membrane Tie-2 protein levels (ANGPTs receptor) (Control: 1.48 ± 0.09 vs OHSS:
2.26 ± 0.17, unidades arbitrarias; p<0.01) in isolated CLs from OHSS group respect
to the control.
On the other hand, in patients
undergoing ART with high probability of developing OHSS, the levels of ANGPT1
increased in follicular fluid (FF) respect to the control group (Control:
149.50 ± 22.11 vs OHSS: 306.20 ± 74.17, pg / ml, p <0.05).
Conclusions: Inhibition of VEGF in the OHSS model affects the follicular and luteal
development, leading to a lower number of CL. In turn, the treatment with a VEGF
inhibitor agonist decreased the severity of OHSS in a rat model. Finally, the
ANGPT-1 together with VEGF, could be used as predictive markers of OHSS.