INVESTIGADORES
PARBORELL Maria Fernanda Agustina
congresos y reuniones científicas
Título:
Involvement of Angiopoietin-1 (angpt-1) in Ovarian Hyperstimulation Syndrome (ohss) Pathogenesis.
Autor/es:
F. PARBORELL; SCOTTI L; ABRAMOVICH D; PASCUALI N; DE ZÚÑIGA I; M. TESONE
Lugar:
Pennsilvania
Reunión:
Congreso; 45th SSR Annual Meeting and the 18th Ovarian Workshop; 2012
Institución organizadora:
Society for the Study of Reproduction (SSR)
Resumen:
OHSS is an iatrogenic complication
associated with ovarian stimulation for the treatment of infertility. Risk factors include low body weight, high
follicle count and elevated serum estradiol. Vasoactive substances such as
vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANGPT1) are
involved in the regulation of vascularization. The ANGPTs/Tie-2 system acts in
concert with VEGF. ANGPT-1 stabilizes blood vessels while ANGPT2 and the
soluble receptor Tie-2 (sTie-2) act as natural antagonists for ANGPT1. The balance
between ANGPT1, ANGPT2, sTie-2 and VEGF is central for ovarian angiogenesis. We
have previously demonstrated that levels of ANGPT1 are increased while levels
of sTie-2 are invariant in fluid follicular (FF) from women at risk of OHSS in
contrast with FF from normoresponders. Our aims were to analyze: 1) the levels
of ANGPT2 in FF from patients at risk of OHSS and 2) the effect of ANGPT1
neutralizing antibody on endothelial cell migration and claudin-V expression in
the presence of FF from patients at risk of developing OHSS. This study was performed
in 51 patients aged 25-39 years old undergoing ART. Patients with pelvic
pathologies such as endometriosis, uterine fibroids or pelvic inflammatory
disease were excluded. The patients were classified into: control group (n=20)
and OHSS group (n=19). The criteria to consider a patient at risk of developing
OHSS were: serum E2 levels >3,000 pg/ml on the day of hCG administration and
a retrieval of >20 oocytes. The FF was centrifuged for 10 min at 2000xg to
remove cellular components. The supernatant was stored at ?80º C until assayed.
The levels of ANGPT2 and claudin-V (tight junction protein) in FF were measured
by western blot. To assess the effect of ANGPT1 on ovarian angiogenesis, we
evaluated the effect of FF from OHSS patients on endothelial cell migration in
the presence of a neutralizing antibody against ANGPT1. For this purpose, a
wound healing assay using the EA.hy926 endothelial cell line was performed. The
levels of ANGPT2 were similar in patients at risk of OHSS compared to control
patients (p<0.01). In addition, the increased levels of ANGPT1 confirmed
those obtained by ELISA in our previous study (p<0.05). There was a marked
increase in the ANGPT1:ANGPT2 ratio in
FF from patients at risk of OHSS compared to control group. FF from patients at
risk of OHSS induced endothelial cell migration at a higher extent than in
normoresponder patients (p<0.001). Incubation with FF from OHSS group in the
presence of an ANGPT1 antibody resulted in a significant decrease in cell
migration compared to those FF without antibody (p<0.05). Moreover, incubation
with FF from OHSS patients in presence of ANGPT-1 antibody produced an increase
in the endothelial levels of claudin-V, in comparison with FF in absence of
antibody (p<0.01). In conclusion, the ANGPTs/Tie-2 system is associated with
the pathogenesis of OHSS. The balanced levels of these proteins are required for
proper ovarian vascular function. Furthermore, the increased endothelial levels
of claudin-V in presence of FF from patients at high risk of OHSS and incubated
with ANGPT1 antibody suggest a decrease in the vascular permeability, partially
regulated by ANGPT1. Therefore, the results described regarding endothelial
cell migration may provide new insights into the mechanisms by which ANGPT1 has
an effect on ovarian disorders such as OHSS.
Supported by: ANPCyT (PICT 2008) and Roemmers Fundation (2009-2011).