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 ZÚÑIGA I; SCOTTI L; ABRAMOVICH D; HORTON M; BISIOLI; TESONE M; PARBORELL F
Reunión:
Encuentro; 27th Annual Meeting-European Society of Human Reproduction and Embryology (ESHRE); 2011
Institución organizadora:
Society of Human Reproduction and Embryology
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. Supported by: Roemmers Fundation, CONICET (PIP 1223) and ANPCYT (PICT 2008/747).