Divergent regulation of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor by hypoxia and female sex steroids in human endometrial stromal cells

作者：Tsuzuki Tomoko; Okada Hidetaka^*; Cho Hisayuu; Shimoi Kayo; Miyashiro Hiroe; Yasuda Katsuhiko; Kanzaki Hideharu

来源：European Journal of Obstetrics & Gynecology and Reproductive Biology, 2013, 168(1): 95-101.

DOI：10.1016/j.ejogrb.2012.12.040

• Angiopoietin
• VEGF
• Hypoxia
• Female sex steroids
• Endometrial stromal cells

Objective: To investigate whether hypoxia or the female sex steroids exert direct effects on angiopoietin-1 (ANGPT1), ANGPT2, and vascular endothelial growth factor (VEGF) in human endometrial stromal cells (ESCs) to clarify the regulatory function of these local angiogenic factors in the endometrium.
Study design: Human endometrial tissues were obtained from 18 patients aged 34-47 years undergoing hysterectomy for benign reasons. ESCs were cultured under hypoxic condition or treated with 17 beta-estradiol (E) and/or medroxyprogesterone acetate (MPA). The mRNA levels and production of ANGPT1, ANGPT2, and VEGF were assessed by real-time RT-PCR and ELISA, respectively. Analysis of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and estrogen receptor alpha (ER alpha) protein levels were evaluated by Western blot analysis.
Result(s): Hypoxia reduced the mRNA expression and protein production of ANGPT-1 in ESCs, whereas those of ANGPT2 were unaffected, resulting in an increase of the ANGPT2/ANGPT1 ratio. Hypoxia induced mRNA expression and protein production of VEGF. E simultaneously induced VEGF production and suppressed ANGPT1 production, resulting in an increase of the ANGPT2/ANGPT1 ratio. MPA or E + MPA reduced ANGPT2 production and sustained the levels of ANGPT1, resulting in a decrease of the ANGPT2/ANGPT1 ratio. With regard to the interaction of E and hypoxia, E did not affect the regulation of angiogenic factors, HIF-1 alpha, and ER alpha under hypoxic conditions.
Conclusions: Hypoxia and female sex hormones independently regulate the ANGPT2/ANGPT1 ratio and VEGF expression in human ESCs. These results may indicate a potential mechanism for hypoxia or female sex steroids influencing angiogenesis in the human endometrium.

• 出版日期2013-5