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Estrogen Receptor- Overexpression Suppresses 17β-Estradiol-Mediated Vascular Endothelial Growth Factor Expression and Activation of Survival Kinases

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, College Station, Texas 77843-1114

Address all correspondence and requests for reprints to: Farida Sohrabji, Texas A&M Health Science Center College of Medicine, 228 Reynolds Medical Building, College Station, Texas 77843-1114. E-mail: sohrabji{at}medicine.tamhsc.edu.

Estrogen and its receptors influence growth and differentiation by stimulating the production and secretion of growth factors. Our previous studies indicate an increased expression of estrogen receptor (ER)- and decreased growth factor synthesis in the olfactory bulb of reproductive senescent female rats as compared with young animals. The present study tests the hypothesis that abnormal overexpression of ER contributes to decreased growth factor synthesis. We developed the HeLa-Tet-On cell line stably transfected with ER (HTER) that expresses increasing amounts of ER with increasing doses of doxycycline (Dox). Increasing doses of Dox had no effect on vascular endothelial growth factor (VEGF) secretion in HTER cells. However, in the presence of 40 nM 17β-estradiol, VEGF secretion increased in low-dose Dox-exposed HTER cultures, which was attenuated by the ER antagonist, 1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]1H-pyrazole dihydrochloride. However, at high-dose Dox and, consequently, high ER levels, estradiol failed to increase VEGF. In the HeLa X6 cell line in which the Tet-On construct is upstream of an unrelated gene (Pitx2A), estradiol failed to induce VEGF at any Dox dose. Furthermore, in the HTER cell line, estradiol selectively down-regulates phospho-ERK2 and phospho-Akt at high ER expression. This study clearly demonstrates that the dose of receptor critically mediates estradiol’s ability to regulate growth factors and survival kinases. The present data also support the hypothesis that 17β-estradiol treatment to an ER overexpressing system, such as the senescent brain, could reverse the normally observed beneficial effect of estrogen.

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