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(American Journal of Pathology. 2007;170:1561-1572.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060926

Luteogenic Hormones Act through a Vascular Endothelial Growth Factor-Dependent Mechanism to Up-Regulate ₅ß₁ and _vß₃ Integrins, Promoting the Migration and Survival of Human Luteinized Granulosa Cells

Alexandra Rolaki^*, George Coukos, Dimitris Loutradis, Horace M. DeLisser, Christos Coutifaris and Antonis Makrigiannakis^*

From the Laboratory of Human Reproduction,^* Department of Obstetrics and Gynaecology, Medical School, University of Crete, Heraklion, Greece; the Division of Human Reproduction, Department of Obstetrics and Gynaecology, and the Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; the Department of Obstetrics and Gynaecology, Medical School, University of Athens, Athens, Greece

The formation of the corpus luteum (CL) is critical for the establishment of a successful pregnancy. After ovulation, the CL develops from the remnants of the ovulated ovarian follicle. This process, which involves varying cell-matrix interactions, is poorly characterized. To understand the role and potential regulation of cell-matrix interactions in the formation of the CL, we investigated the expression and activity of the matrix protein fibronectin (FN) and several of its integrin receptors on luteinized granulosa cells (GCs). In situ, FN and several FN-binding integrins were detected around luteinizing GCs during the early luteal phase, although expression declined in the late luteal phase. In vitro, GCs released FN, and stimulation of these cells with human chorionic gonadotropin increased the surface expression of FN, ₅ß₁, and _vß₃. Up-regulation of these proteins on GCs was reproduced by stimulation with vascular endothelial growth factor (VEGF) and was inhibited by anti-VEGF antibody. Lastly, expression of ₅ß₁ and _vß₃ mediated adhesion to FN, facilitated migration, and prevented apoptosis. These data suggest that in vivo luteogenic hormones, in part through a VEGF-dependent mechanism, stimulate selected integrin-matrix adhesive interactions that promote the motility and survival of GCs and thus contribute to the formation and preservation of the CL.