title: Administration of vascular endothelial growth factor Trap during the 'post-angiogenic' period of the luteal phase causes rapid functional luteolysis and selective endothelial cell death in the marmoset.
abstract: The intense angiogenesis characteristic of early corpus luteum development is dependent upon vascular endothelial growth factor (VEGF) as inhibitors of VEGF administered at the peri-ovulatory period suppress endothelial cell proliferation and progesterone secretion. We now report that administration of VEGF Trap, a soluble decoy receptor-based inhibitor, at the mid- or the late luteal phase in the marmoset results in a rapid decline in plasma progesterone. Since vascularisation of the corpus luteum is largely complete by the mid-luteal phase, it suggested that this functional luteolysis involved mechanisms other than inhibition of angiogenesis. A second experiment investigated the role of VEGF in maintaining the integrity of the luteal vasculature and hormone-producing cells. VEGF Trap was administered to marmosets in the mid-luteal phase and ovaries were obtained 1, 2, 4 or 8 days later for localisation of activated caspase-3 staining in the corpus luteum and compared with those obtained 2, 4 and 8 days after administration of control protein. The number of cells with activated caspase-3 staining was significantly increased after administration of VEGF Trap. Dual staining of activated caspase-3 with the endothelial cell marker CD31 showed that at 1 day post-treatment, more than 90% caspase-3-stained cells were vascular endothelium, prior to detection of an increasing incidence in death of hormone-producing cells on days 2 and 4. Staining with CD31 showed that the endothelial cell area was decreased after treatment. By 8 days after treatment, corpora lutea had regressed to varying degrees, while all control corpora lutea remained healthy. These results show that VEGF inhibition in the mid- or the late luteal phase induces functional luteolysis in the marmoset that is associated with premature and selective death of endothelial cells.
authors.affiliation: Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. h.fraser@hrsu.mrc.ac.uk
authors.forename: Hamish M
authors.initials: HM
authors.lastname: Fraser
authors.forename: Helen
authors.initials: H
authors.lastname: Wilson
authors.forename: Christine
authors.initials: C
authors.lastname: Wulff
authors.forename: John S
authors.initials: JS
authors.lastname: Rudge
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Wiegand
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002144:Callithrix; D016923:Cell Death; D003338:Corpus Luteum / Q000098:blood supply* / Q000166:cytology / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology*; D005260:Female; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry / Q000379:methods; D008183:Luteal Phase; D003341:Luteolysis; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011374:Progesterone / Q000097:blood; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; C460365:VEGF Trap R1R2 protein; D042461:Vascular Endothelial Growth Factor A; D011374:Progesterone