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Regulation of Angiogenic Activity of Human Endometrial Endothelial Cells in Culture by Ovarian Steroids

Department of Obstetrics and Gynecology, Yale University School of Medicine (U.A.K, J.L., O.G.-K., Y.S., A.A.), New Haven, Connecticut 06520-8063; and Departments of Histology and Embryology (U.A.K., Y.S., R.D.) and Medical Biology and Genetics (O.G.-K.), Akdeniz University School of Medicine, Antalya 07070, Turkey

Address all correspondence and requests for reprints to: Dr. Aydin Arici, Section of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063. E-mail: aydin.arici{at}yale.edu.

Blood vessel growth and regression in human endometrium are regulated throughout the menstrual cycle. We sought a direct role of ovarian steroids on human endometrial endothelial cell (HEEC) proliferation and vascularization. To investigate the HEEC angiogenicity of sex steroids, we developed a reliable method for the isolation of HEEC, which allowed us to investigate the angiogenic effects of sex steroids using immunohistochemistry, immunocytochemistry, Western blot, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt proliferation, and vascular tube formation analyses. We were able to obtain 95–99% pure HEEC with our isolation technique. HEEC expressed predominantly estrogen receptor ß, minimally expressed estrogen receptor , and but did not express progesterone (P₄) receptors A and B in vivo and in vitro. Estradiol (E₂; 10^–10–10^–8 M) and P₄ (10^–12–10^–8 M), alone or in combination, induced HEEC proliferation compared with control values after 48 h of treatment (P < 0.05). Furthermore, after 8 d of treatment, there were significantly more angiogenic patterns in E₂ (10^–8 M), P₄ (10^–10 M), and E₂ plus P₄ (10^–8 and 10^–10 M) treatment groups compared with the control group (angiogenic scores, 2.95 ± 0.16, 3.26 ± 0.16, 3.06 ± 0.17, and 1.93 ± 0.15, respectively; P < 0.01). In conclusion, our results suggest that there are direct effects of E₂ and P₄ on HEEC and provide a new understanding of the physiological role of sex steroids in the regulation of endometrial events such as angiogenesis.

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