TY - JOUR
T1 - Uterine expression of vascular endothelial growth factor is increased by estradiol and tamoxifen
AU - Hyder, Salman M.
AU - Stancel, George M.
AU - Chiappetta, Constance
AU - Murthy, Lata
AU - Boettger-Tong, Holly L.
AU - Makela, Sari
PY - 1996/9/1
Y1 - 1996/9/1
N2 - Vascular endothelial growth factor (VEGF) is an endothelial-specific mitogen with potent angiogenic activity. Because vascular growth accompanies normal endometrial regeneration and may also be involved in uterine tumor growth, we studied VEGF regulation by 17β-estradiol (E2) and tamoxifen, two agents that ran increase uterine cell proliferation and tumor incidence. In immature, ovariectomized rats, E2 elevates uterine VEGF mRNA transiently, with a peak induction of 15-20-fold within 1 h. A maximum response is produced at a dose of 4 μg/kg E2, and induction is specific for estrogenic steroids. E2-dependent VEGF induction is inhibited by actinomycin D but not puromycin, suggesting that the effect is due at least in part to direct estrogen receptor regulation of VEGF transcription. PCR amplification and DNA sequencing indicated that VEGF188, VEGF164 and VEGF120 are all induced by E2, but the latter two are the predominant forms in the uterus. In situ hybridization shows a predominantly stromal expression of VEGF mRNA. The antiestrogens tamoxifen, 4-OH tamoxifen, and nafoxidine produce similar increases in uterine VEGF mRNA levels within 6 h, with 1 mg/kg tamoxifen producing a maximum response of 15-20-fold. The tamoxifen response was also inhibited by actinomycin D but not by puromycin, again suggesting direct transcriptional regulation of VEGF expression by antiestrogens. These findings raise the possibility that estrogen and antiestrogen effects on uterine edema, proliferation, and tumor incidence may involve local increases in tissue VEGF production.
AB - Vascular endothelial growth factor (VEGF) is an endothelial-specific mitogen with potent angiogenic activity. Because vascular growth accompanies normal endometrial regeneration and may also be involved in uterine tumor growth, we studied VEGF regulation by 17β-estradiol (E2) and tamoxifen, two agents that ran increase uterine cell proliferation and tumor incidence. In immature, ovariectomized rats, E2 elevates uterine VEGF mRNA transiently, with a peak induction of 15-20-fold within 1 h. A maximum response is produced at a dose of 4 μg/kg E2, and induction is specific for estrogenic steroids. E2-dependent VEGF induction is inhibited by actinomycin D but not puromycin, suggesting that the effect is due at least in part to direct estrogen receptor regulation of VEGF transcription. PCR amplification and DNA sequencing indicated that VEGF188, VEGF164 and VEGF120 are all induced by E2, but the latter two are the predominant forms in the uterus. In situ hybridization shows a predominantly stromal expression of VEGF mRNA. The antiestrogens tamoxifen, 4-OH tamoxifen, and nafoxidine produce similar increases in uterine VEGF mRNA levels within 6 h, with 1 mg/kg tamoxifen producing a maximum response of 15-20-fold. The tamoxifen response was also inhibited by actinomycin D but not by puromycin, again suggesting direct transcriptional regulation of VEGF expression by antiestrogens. These findings raise the possibility that estrogen and antiestrogen effects on uterine edema, proliferation, and tumor incidence may involve local increases in tissue VEGF production.
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M3 - Article
C2 - 8752163
AN - SCOPUS:0029794465
SN - 0008-5472
VL - 56
SP - 3954
EP - 3960
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -