title: Slit2/Robo4 Signaling: Potential Role of a VEGF-Antagonist Pathway to Regulate Luteal Permeability.
abstract: IntroductionThe corpus luteum (CL) is dependent on luteal vascular permeability, which is controlled by human chorionic gonadotropin (hCG) via vascular endothelial growth factor (VEGF). In this study we investigated the role of a potential VEGF antagonist pathway - Slit2/Robo4 - and its influence on endothelial cell adhesion.Materials and MethodsLuteinized granulosa cells (LGCs) were stimulated with hCG in the absence or presence of a VEGF inhibitor. The expression of VEGF and Slit2 were measured. Human umbilical vein endothelial cells (HUVECs) were stimulated with Slit2 or VEGF, and gene expressions of cadherin 5 (CDH5) and claudin 5 (CLDN5) were measured. Following Robo4 knockdown, CDH5, CLDN5 and endothelial permeability were measured.ResultsStimulation of human LGCs with hCG significantly increased VEGF while Slit2 expression was significantly suppressed. Inhibition of VEGF action after hCG stimulation did not change Slit2 suppression. Slit2 knockdown did not affect VEGF expression. While VEGF stimulation of HUVECs significantly suppressed CDH5 and CLDN5 gene expression, stimulation of HUVECs with Slit2 resulted in a significant increase in CDH5 and CLDN5. Robo4 knockdown was done, leading to downregulation of CDH5 and CLDN5 which resulted in significantly increased permeability.ConclusionsOur results indicate the existence of a VEGF-antagonist pathway in the CL that decreases vascular permeability. During the functional life of the CL the pathway is suppressed by hCG. It is possible that stimulation of this pathway could be used to treat ovarian hyperstimulation syndrome.
authors.affiliation: University of Ulm, Department of Gynecology and Obstetrics, Ulm, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Bekes
authors.affiliation: University Children's Hospital Zurich, Department of Pediatric Stem Cell Transplantation, Zurich, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Haunerdinger
authors.affiliation: University of Ulm, Department of Gynecology and Obstetrics, Ulm, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Sauter
authors.affiliation: University of Ulm, Department of Gynecology and Obstetrics, Ulm, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Holzheu
authors.affiliation: University of Ulm, Department of Gynecology and Obstetrics, Ulm, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Janni
authors.affiliation: University of Würzburg, Department of Gynecology and Obstetrics, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Wöckel
authors.affiliation: University of Würzburg, Department of Gynecology and Obstetrics, Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Wulff
keywords: OHSS; Slit2; VEGF; hCG; luteal permeability