title: Vascular endothelial growth factor mediates the estrogen-induced breakdown of tight junctions between and increase in proliferation of microvessel endothelial cells in the baboon endometrium.
abstract: To assess whether there is a link between estrogen, vascular endothelial growth factor (VEGF), and early aspects of uterine angiogenesis, an acute temporal study was conducted in which ovariectomized baboons were pretreated with VEGF Trap, which sequesters endogenous VEGF, and administered estradiol at time 0 h. Serum estradiol levels approximated 500 pg/ml 4-6 h after estradiol administration. VEGF mRNA levels in endometrial glandular epithelial and stromal cells were increased to values 6 h after estradiol that were 3.74 +/- 0.99-fold (mean +/- se) and 5.70 +/- 1.60-fold greater (P < 0.05), respectively, than at 0 h. Microvessel interendothelial cell tight junctions, which control paracellular permeability, were present in the endometrium at time 0 h, but not evident 6 h after estradiol administration. Thus, microvessel paracellular cleft width increased (P < 0.01, ANOVA) from 5.03 +/- 0.22 nm at 0 h to 7.27 +/- 0.48 nm 6 h after estrogen. In contrast, tight junctions remained intact, and paracellular cleft widths were unaltered in estradiol/VEGF Trap and vehicle-treated animals. Endometrial microvessel endothelial cell mitosis, i.e. percent Ki67+/Ki67- immunolabeled endothelial cells, increased (P < 0.05) from 2.9 +/- 0.3% at 0 h to 21.4 +/- 7.0% 6 h after estrogen treatment but was unchanged in estradiol/VEGF Trap and vehicle-treated animals. In summary, the estrogen-induced disruption of endometrial microvessel endothelial tight junctions and increase in endothelial cell proliferation were prevented by VEGF Trap. Therefore, we propose that VEGF mediates the estrogen-induced increase in microvessel permeability and endothelial cell proliferation as early steps in angiogenesis in the primate endometrium.
authors.affiliation: Department of Obstetrics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Graham W
authors.initials: GW
authors.lastname: Aberdeen
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Wiegand
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bonagura
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Pepe
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Albrecht
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004717:Endometrium / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D046529:Microscopy, Electron, Transmission; D055806:Microvessels / Q000166:cytology / Q000502:physiology; D010052:Ovariectomy; D010215:Papio; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D014841:von Willebrand Factor / Q000032:analysis / Q000276:immunology
chemical_list: D019394:Ki-67 Antigen; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C029417:Von Willebrand antigen; D014841:von Willebrand Factor; D004958:Estradiol