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Stathmin, a Microtubule Regulatory Protein, Is Associated with Hypoxia-Inducible Factor-1 Levels in Human Endometrial and Endothelial Cells

Department of Endocrine Pharmacology (M.Y., E.M., K.T.), Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan; and Department of Obstetrics and Gynecology (S.K.), School of Medicine, Kanazawa University, Ishikawa 920-8641, Japan

Address all correspondence and requests for reprints to: Kazuhiro Tamura, Ph.D., Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail: hiro{at}ps.toyaku.ac.jp.

Local hypoxia that occurs during menstruation triggers angiogenesis that is crucial for cyclical remodeling of the endometrium during the menstrual cycle. Hypoxia is thought to be important for the expression of vascular endothelial growth factor (VEGF) via its transcriptional factor, hypoxia inducible factor (HIF)-1, in the endometrium. The activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway may modulate HIF-1 protein levels. Stathmin, a microtubule regulatory protein, was expressed in the stroma, glandular epithelium, and vascular endothelium in human endometrium. In this study, we examined a possible role of stathmin in hypoxia-induced HIF-1 and VEGF expression in primary isolated and immortalized human endometrial stromal cells, glandular epithelial cells, and human umbilical venous endothelial cells (HUVEC). Knocking down stathmin expression using small interfering RNA caused microtubule stabilization and inhibited hypoxia-induced VEGF mRNA expression via the reduction of HIF-1 protein levels in endometrial cells and HUVEC. Treatment of the cells with a PI3K inhibitor, wortmannin, inhibited the expression of VEGF mRNA and the accumulation of HIF-1 protein. Silencing of stathmin expression repressed the activation (phosphorylation) of Akt in endometrial cells and HUVEC. These results suggest that endometrial stathmin is linked to HIF-1 protein accumulation and VEGF expression through the PI3K/Akt signaling pathway and may be involved in regeneration of the endometrium during the menstrual cycle in human uterine cells.