UTERINE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IS INCREASEDBY ESTRADIOL AND TAMOXIFEN

Vascular endothelial growth factor (VEGF) is an endothelial-specific m itogen with potent angiogenic activity. Because vascular growth accomp anies normal endometrial regeneration and may also be involved in uter ine tumor growth, we studied VEGF regulation by 17 beta-estradiol (E(2 )) and tamoxifen, two agents that can increase uterine cell proliferat ion and tumor incidence. In immature, ovariectomized rats, E(2) elevat es 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 mu g/kg E(2) , and induction is specific for estrogenic steroids, E(2)-dependent VE GF induction is inhibited by actinomycin D but not puromycin, suggesti ng that the effect is due at least in part to direct estrogen receptor regulation of VEGF transcription. PCR amplification and DNA sequencin g indicated that VEGF(188), VEGF(164), and VEGF(120) are all induced b y E(2), but the latter two are the predominant forms in the uterus, In situ hybridization shows a predominantly stromal expression of VEGF m RNA. The antiestrogens tamoxifen, 4-OH tamoxifen, and nafoxidine produ ce similar increases in uterine VEGF mRNA levels within 6 h, with 1 mg /kg tamoxifen producing a maximum response of 15-20-fold. The tamoxife n response was also inhibited by actinomycin D but not by puromycin, a gain suggesting direct transcriptional regulation of VEGF expression b y antiestrogens. These findings raise the possibility that estrogen an d antiestrogen effects on uterine edema, proliferation, and tumor inci dence may involve local increases in tissue VEGF production.