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Uterine Expression of Vascular Endothelial Growth Factor Is Increased by Estradiol and Tamoxifen¹

Departments of Pharmacology [S. M. H., G. M. S., C. C., L. M., H. L. B-T., S. M.], Obstetrics, Gynecology, and Reproductive Sciences [S. M. H.], University of Texas Medical School, Houston, Texas 77225 and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030 [L. M.]

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 17ß-estradiol (E₂) and tamoxifen, two agents that can 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.

¹ This research was supported by a Grant-in-Aid from the American Heart Association, Texas Affiliate, and by NIH Grants HD-08615 and ES-06995.

² To whom requests for reprints should be addressed, at Department of Pharmacology, University of Texas Medical School, 6431 Fannin, P.O. Box 20708, Houston, TX 77225.

Received 3/25/96. Accepted 7/ 2/96.

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