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

被引:35
作者
Aberdeen, Graham W. [1 ,4 ,5 ]
Wiegand, Stanley J. [2 ]
Bonagura, Thomas W., Jr. [1 ,4 ,5 ]
Pepe, Gerald J. [3 ]
Albrecht, Eugene D. [1 ,4 ,5 ]
机构
[1] Univ Maryland, Sch Med, Ctr Studies Reprod, Dept Obstet, Baltimore, MD 21201 USA
[2] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA
[3] Eastern Virginia Med Sch, Dept Physiol Sci, Norfolk, VA 23507 USA
[4] Univ Maryland, Sch Med, Ctr Studies Reprod, Dept Gynecol, Baltimore, MD 21201 USA
[5] Univ Maryland, Sch Med, Ctr Studies Reprod, Dept Reprod Sci, Baltimore, MD 21201 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1210/en.2008-0521
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 6h 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 6h 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. (Endocrinology 149: 6076-6083, 2008)
引用
收藏
页码:6076 / 6083
页数:8
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