Regulation of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR by estradiol through VEGF in uterus

The induction of vascular endothelial growth factor (VEGF) expression by 17 beta-estradiol (E-2) in many target cells, including epithelial cells, fibroblasts and smooth muscle cells, suggests a role for this hormone in the modulation of angiogenesis and vascular permeability. We have already described a cyclic increase in Flk-1/KDP-expressing capillaries in the human endometrium during the proliferative and mid-secretory phases, strongly suggestive of an E, effect on Flk-1/KDR expression in the endometrial capillaries. However, it is unclear whether these processes are due to a direct effect of E, on endothelial cells. Using immunohistochemistry, we report an increase in Flk-1/KDR expression in endometrial capillaries of ovariectomized mice treated with E-2, or both E2 and progesterone. This process is mediated through estrogen receptor (ER) activation. hi vitro experiments using quantitative RT-PCR analysis demonstrate that Flk-1/KDR expression was not regulated by E-2 in human endothelial cells from the microcirculation (HMEC-1) or macrocirculation (HUVEC), even in endothelial cells overexpressing ER alpha or ER beta after ER-mediated adenovirus infection. In contrast, Flk-1/KDR expression was up-regulated by VEGF itself, in a time- and dose-dependent manner, with the maximal response at 10 ng/ml. Thus, we suggest that E-2 up-regulates Flk-1/KDR expression in vivo in endothelial cells mainly through the modulation of VEGF by a paracrine mechanism. It is currently unknown whether or not the endothelial origin might account for differences in the E-2-modulation of VEGF receptor expression, particularly in relation to the vascular bed of sex steroid-responsive tissues.