Vascular endothelial growth factor is modulated in vascular muscle cells by estradiol, tamoxifen, and hypoxia

Vascular endothelial growth factor (VEGF) promotes neovascularization, micr ovascular permeability, and endothelial proliferation. We described previou sly VEGF mRNA and protein induction by estradiol (E2) in human endometrial fibroblasts. We report here E2 induction of VEGF expression in human venous muscle cells [smooth muscle cells (SMC) from human saphenous veins; HSVSMC ] expressing both ER-alpha and ER-beta estrogen receptors. E2 at 10(-9) to 10(-8) M increases VEGF mRNA in HSVSMC in a time-dependent manner (3-fold a t 24 h), as analyzed by semiquantitative RT-PCR. This level of induction is comparable with E2 endometrial induction of VEGF mRNA. Tamoxifen and hypox ia also increase HSVSMC VEGF mRNA expression over control values. Immunocyt ochemistry of saphenous veins and isolated SMC confirms translation of VEGF mRNA into protein. Immunoblot analysis of HSVSMC-conditioned medium detect s three bands of 18, 23, and 28 kDa, corresponding to VEGF isoforms of 121, 165, and 189 amino acids. Radioreceptor assay of the conditioned medium pr oduced by E2-stimulated HSVSMC reveals an increased VEGF secretion. Our dat a indicate that VEGF is E2, tamoxifen, and hypoxia inducible in cultured HS VSMC and E2 inducible in aortic SMC, suggesting E2 modulation of VEGF effec ts in angiogenesis, vascular permeability, and integrity.