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Vascular Endothelial Cadherin Regulates Vascular Permeability: Implications for Ovarian Hyperstimulation Syndrome

Instituto Valenciano de Infertilidad-Madrid (A.V., A.Pa., J.A.G.-V.), 28035 Madrid, Spain; Instituto Valenciano de Infertilidad-Valencia (A.R., A.Pe.), 46015 Valencia, Spain; Department of Pediatrics, Obstetrics and Gynecology (A.Pe.), Valencia University School of Medicine, 46010 Valencia, Spain; Department of Obstetrics and Gynecology (A.Pe.), University Hospital Dr. Peset, 46017 Valencia, Spain; and Rey Juan Carlos University (J.A.G.-V.), 28922 Madrid, Spain

Address all correspondence and requests for reprints to: Juan A. Garcia-Velasco, Instituto Valenciano de Infertilidad-Madrid, C/Santiago de Compostela, 88-bajo, 28035 Madrid, Spain. E-mail: jgvelasco{at}ivi.es.

Context: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of treatment with fertility drugs. It is characterized by increased vascular permeability and simultaneous overexpression of vascular endothelial growth factor (VEGF) in ovarian cells.

Objective: We tested the hypothesis that the endothelium and endothelial cell-to-cell junctions are downstream targets of VEGF during OHSS pathogenesis. We investigated the potential involvement of vascular endothelial (VE)-cadherin, an interendothelial adhesion molecule, in the capillary hyperpermeability in OHSS.

Design: Human endothelial cells from umbilical veins (HUVEC) were used as an in vitro model of OHSS.

Intervention: Cell cultures were treated with varying doses of estradiol (E₂), human chorionic gonadotropin (hCG), VEGF, and antihuman VEGF antibodies, either alone or in combination, and the effect on VE-cadherin release was evaluated at different time points. Permeability assays were performed using fluoresceinisothiocyanate-labeled albumin, and actin filaments rearrangement was evaluated by fluorescent microscopy.

Results: Culturing of HUVEC with high doses of E₂ produced no significant changes in VE-cadherin concentration, but hCG and VEGF produced a significant increase in VE-cadherin release. Time-course experiments showed that VE-cadherin was secreted 12 h after VEGF addition. Antihuman VEGF antibodies prevented these changes. Permeability assays demonstrated that, although E₂ did not alter the arrangement of HUVEC in vitro, hCG and VEGF caused changes in the actin fibers indicative of increased capillary permeability. VEGF also induced an increase in paracellular permeability of HUVEC at the same doses used in the previous experiments.

Conclusions: Adhesion molecules like VE-cadherin may play a role in the development and progression of increased capillary permeability in severe OHSS.

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