Sphingosine-1-phosphate restores endothelial barrier integrity in ovarian hyperstimulation syndrome

SCOTTI, L.; DI PIETRO, M.; PASCUALI, N.; IRUSTA, G.; GOMEZ PEÑA, M.; POMILIO, C.; SARAVIA, F.; TESONE, M.; ABRAMOVICH, D.; PARBORELL, F.

MOLECULAR HUMAN REPRODUCTION.

OXFORD UNIV PRESS

Año: 2016

1360-9947

Sphingosine-1-phosphate restores endothelial barrier integrity in ovarianhyperstimulation syndrome.Scotti L(1), Di Pietro M(1), Pascuali N(1), Irusta G(1), I de Zúñiga(2), GomezPeña M(2), Pomilio C(1)(2), Saravia F(1)(2), Tesone M(1)(2), Abramovich D(1),Parborell F(3).Author information: (1)Instituto de Biología y Medicina Experimental (IByME) - CONICET, Vuelta deObligado 2490, C1428ADN, Buenos Aires, Argentina.(2)Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales,Universidad de Buenos Aires, Intendente Güiraldes 2160, C1428EGA, Buenos Aires , Argentina.(3)Instituto de Biología y Medicina Experimental (IByME) - CONICET, Vuelta deObligado 2490, C1428ADN, Buenos Aires, Argentina fparborell@gmail.com.STUDY QUESTION: Are follicular fluid (FF) sphingosine-1-phosphate (S1P) levels inpatients at risk of developing ovarian hyperstimulation syndrome (OHSS) alteredand in part responsible for the high vascular permeability observed in thesepatients.STUDY ANSWER: FF S1P levels are lower in FF from patients at risk of OHSS andtreatment with S1P may reduce vascular permeability in these patients.WHAT IS KNOWN ALREADY: Although advances have been made in the diagnosis, andmanagement of OHSS and in basic knowledge of its development, complete preventionhas proven difficult.STUDY DESIGN, SIZE, DURATION: A total of 40 FF aspirates were collected frompatients undergoing ART. The women (aged 25-39 years old) were classified into a control group (n = 20) or a group at risk of OHSS (n = 20). The EA.hy926endothelial cell line was used to assess the efffects of FF from patients at riskof OHSS with or without the addition of S1P. An animal model that develops OHSSin immature Sprague-Dawley rats were also used.PARTICIPANTS/MATERIALS, SETTING, METHODS: Migration assays, confocal microscopyanalysis of actin filaments, immunoblotting and quail chorioallantoic membrane(CAM) assays of in-vivo angiogenesis were performed and statistical comparisonsbetween groups were made.MAIN RESULTS AND THE ROLE OF CHANCE: The S1P concentration was significantlylower in FF from patients at risk of OHSS (P = 0.03). The addition of S1P to thisFF decreased cell migration (P < 0.05) and prevented VE-cadherin phosphorylation in endothelial cells (P < 0.05). S1P in the FF from patients at risk of OHSSincreased the levels of VE-cadherin (P < 0.05), N-cadherin (P < 0.05) andβ-catenin (P < 0.05), and partially reversed actin redistribution in endothelial cells. The addition of S1P in FF from patients at risk of OHSS also decreased thelevels of vascular endothelial growth factor (VEGF121; P < 0.01) and S1P lyase(SPL; P < 0.05) and increased the levels of S1PR1 (P < 0.05) in endothelialcells. In CAMs incubated with FF from patients at risk of OHSS with S1P, thenumber of vessel branch points decreased while the periendothelial cell coverage increased. Additionally, in a rat OHSS model, we demonstrated that vascularpermeability and VEGF121 and its receptor KDR expression were increased in theOHSS group compared to the control group and that S1P administration decreasedthese parameters.LARGE SCALE DATA: N/A.LIMITATIONS, REASONS FOR CAUTION: The results of this study were generated froman in-vitro system. This model reflects the microvasculature in vivo. Even thoughthe ideal model would be the use of human endothelial cells from the ovary, it isobviously not possible to carry out this kind of approach in ovaries of patients from ART. More studies will be necessary to delineate the effects of S1P in thepathogenesis of OHSS. Hence, clinical studies are needed in order to choose themost appropriate method of prevention and management.WIDER IMPLICATIONS OF THE FINDINGS: The use of bioactive sphingolipid metabolitesmay contribute to finding better and safer therapeutic strategies for thetreatment of OHSS and other human diseases that display aberrant vascularleakage.STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants ANPCyT (PICT2012-897), CONICET (PIP 5471), Roemmers and Baron Foundation, Argentina. Theauthors declare no conflict of interest.© The Author 2016. Published by Oxford University Press on behalf of the EuropeanSociety of Human Reproduction and Embryology. All rights reserved.ForPermissions, please email: journals.permissions@oup.com.