Ovarian steroids in endometrial angiogenesis

Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is fundamental for human endometrial development and differentiation, which a re necessary for implantation. This vascular process is supposed to be main ly mediated by the vascular endothelial growth factor (VEGF), also named va scular permeability factor (VPF). We report here the expression and modulat ion of VEGF and its receptors, Flk-1/KDR and Flt-1, in the functionalis thr oughout the menstrual cycle. Using immunocytochemistry, VEGF is localized i n glandular epithelial cells and in the surrounding stroma, as well as in c apillaries and spiral arterioles. The localization of VEGF on the endotheli um correlates with the presence of Flt-1 and Flk-1/KDR receptors on vascula r structures, including capillary strands that have not yet formed a lumen and that have been previously described in tumors as angiogenic capillaries . The strongest immunoreactivity for both VEGF and Flk-1/KDR receptor on en dothelial cells is detected in the proliferative and midsecretory phases. E nhanced expression of VEGF and its Flk-1 receptors on narrow capillary stra nds during the proliferative phase may account for the rapid capillary grow th associated with endometrial regeneration from the residual basal layer f ollowing menstrual shedding of the functionalis. The vascular expression of Flt-1 is more important in the secretory than in the proliferative phase, associated with a high microvascular density and an increase in vascular pe rmeability in the implantation period. Consistently with these in vivo obse rvations, the treatment of isolated endometrial stromal cells with estradio l (E-2). Or E-2 + progesterone, significantly increased VEGF mRNA over the control value in a dose-dependent manner. These results demonstrate that th e expression of VEGF and its receptors is cyclically modulated by ovarian s teroids, and that this endothelial growth factor acts on the endothelium in a paracrine fashion to control endometrial angiogenesis and permeability. (C) 2000 Elsevier Science inc. All rights reserved.