In vivo intrabursal administration of bioactive lipid sphingosine- 1-phosphate enhances vascular integrity in a rat model of ovarian hyperstimulation syndrome

PARBORELL, FERNANDA; MAY, MARÍA; SCOTTI, LEOPOLDINA; TESONE, MARTA; PARBORELL, FERNANDA; IRUSTA, GRISELDA; MAY, MARÍA; PIETRO, MARIANA DI; SCOTTI, LEOPOLDINA; TESONE, MARTA; IRUSTA, GRISELDA; PIETRO, MARIANA DI; ABRAMOVICH, DALHIA; BAS, DIANA; PASCUALI, NATALIA; ABRAMOVICH, DALHIA; BAS, DIANA; PASCUALI, NATALIA

MOLECULAR HUMAN REPRODUCTION.

OXFORD UNIV PRESS

Año: 2017 vol. 23 p. 417 - 427

1360-9947

STUDY QUESTION: Can the bioactive lipid sphingosine-1 phosphate (SIP) act as an endothelial barrier-enhancing molecule and, in turn, restore the vascular integrity and homoeostasis in a rat model of ovarian hyperstimulation syndrome (OHSS). STUDY ANSWER: In vivo administration of SIP may prevent the early onset of OHSS and decrease its severity. WHAT IS KNOWN ALREADY: Although advances in the prediction and treatment of OHSS have been made, complete prevention has not been possible yet. SIP in follicular fluid from women at risk of developing OHSS are lower in comparison from women who are not at such risk and administration of SIP in an OHSS rat model decreases ovarian capillary permeability. STUDY DESIGN, SIZE, DURATION: We used an animal model that develops OHSS in immature Sprague-Dawley rats. The rats were randomly divided into three groups: The control group, which was injected with 10 IU of pregnant mare´s serum gonadotropin (PMSG), and 10 IU of hCG 48 h later; the OHSS group, which was injected with excessive doses of PMSG (50 lU/day) for four consecutive days, followed by hCG; and the OHSS + SIP group, which was injected with the same doses of PMSG and hCG as the OHSS group and then treated with 5 pl SIP (I mM) under the bursa of both ovaries, whereas the other groups of animals received the SIP vehicle. PARTICIPANTS /MATERIALS, SETTING, METHODS: Rats were killed by decapitation 48 h after the hCG injection for ovary, endometrium and blood collection. The ovaries were weighed and then used for subsequent assays, while the serum was used for hormone assays. One of the ovaries from each rat (n = 6) was used for Western immunoblot and the other for immunohistochemical analysis. Statistical comparisons between groups were carried out. MAIN RESULTS AND THE ROLE OF CHANCE: SIP administration reduced the ovarian weight (P < 0.05), and decreased the concentration of serum progesterone in the OHSS group compared to the OHSS group without treatment (P < 0.00I). The percentage of antral follicles in the OHSS group was lower than that in the control group. SIP increased the percentage of antral follicles (P < 0.05) and decreased the percentage of corpora lutea (P < 0.0I) and cystic structures in the OHSS group (P < 0.05). SIP had no effect on the expression levels of the enzymes 3p-hydroxysteroid dehydrogenase (3pHSD) or cholesterol side-chain cleavage enzyme (P450scc), but reduced the levels of steroidogenic acute regulatory protein (StAR) in OHSS rat ovaries (P < 0.05). SIP decreased the endothelial (P < 0.05) and periendothelial (P < 0.0I) cell area in OHSS rat ovaries. SIP restored the levels of N-cadherin and VE-cadherin proteins to control values. Furthermore, SI P enhanced the levels of claudin-5, occludin (P < 0.05) and sphingosine- 1-phosphate receptor 1 (SIPRI) in OHSS (P < 0.01). In addition, no histological differences were found in endometrium between OHSS and SI P-treated OHSS animals. LIMITATIONS REASONS FOR CAUTION: The results of this study were generated from an in vivo OHSS experimental model, which has been used by several authors and our group due to the similarity between the rat and human angiogenic systems. Further studies in patients will be needed to evaluate the effects of SIP in the pathogenesis of OHSS. WIDER IMPLICATIONS OF THE FINDINGS: These findings concern the pathophysiological importance of SIP in OHSS. More studies on the regulation of endothelial cell barrier function by SIP in reproductive pathological processes and its therapeutic application are required. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by grants from ANPCyT (PICT 20I2-897), CONICET (PIP 547I), Roemmers and Baron Foundations, Argentina. The authors declare no conflicts of interest.