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The Role of Vascular Endothelial Growth Factor and Estradiol in the Regulation of Endometrial Angiogenesis and Cell Proliferation in the Marmoset

Medical Research Council Human Reproductive Sciences Unit (H.M.F., H.W., A.S., K.D.M.), University of Edinburgh Centre for Reproductive Biology, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; and Regeneron Pharmaceuticals (S.J.W.), Tarrytown, New York 10591

Address all correspondence and requests for reprints to: Hamish M Fraser, Medical Research Council, Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: h.fraser{at}hrsu.mrc.ac.uk.

The present studies explore the roles of vascular endothelial growth factor (VEGF) and estradiol on angiogenesis and stromal and epithelial cell proliferation in the marmoset endometrium during the proliferative phase of the ovulatory cycle. At the start of the proliferative phase, marmosets were 1) treated with vehicle, 2) treated with a VEGF inhibitor (VEGF Trap, aflibercept), 3) ovariectomized, 4) ovariectomized and given replacement estradiol, or 5) treated with VEGF Trap and given replacement estradiol. The uterus was examined 10 d later in the late proliferative phase. Changes in endothelial and epithelial cell proliferation were quantified using a volumetric density method after immunohistochemistry for bromodeoxyuridine to localize proliferating cells, CD31 to visualize endothelial cells, and dual staining to distinguish endothelial cell proliferation. Endothelial proliferation was elevated in late proliferative controls but virtually absent after VEGF Trap. Ovariectomy had a similar inhibitory effect, whereas angiogenesis was restored by estrogen replacement. Estradiol replacement in VEGF Trap-treated marmosets resulted in only a small increase in endothelial cell proliferation that remained significantly below control values. VEGF Trap treatment and ovariectomy also markedly reduced stromal cell proliferation but resulted in increased stromal cell density associated with a reduction in overall endometrial volume. Estrogen replacement in both ovariectomized and VEGF Trap-treated animals restored stromal proliferation rates and cell density. These results show that endometrial angiogenesis and stromal proliferation during the proliferative phase are driven by estradiol and that the effect of estrogen on angiogenesis is mediated largely by VEGF.

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