PATTERNS OF EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) AND VEGF RECEPTORS IN MICE SUGGEST A ROLE IN HORMONALLY REGULATED ANGIOGENESIS

Vascular endothelial growth factor (VEGF) is a secreted endothelial ce ll-specific mitogen. To evaluate whether VEGF may play a role in angio genesis, we have determined the spatial and temporal patterns of expre ssion of VEGF and VEGF receptors during natural angiogenic processes t aking place within the female reproductive system. Four angiogenic pro cesses were analyzed: neovascularization of ovarian follicles, neovasc ularization of the corpus luteum, repair of endometrial vessels, and a ngiogenesis in embryonic implantation sites. During all processes, VEG F mRNA was found to be expressed in cells surrounding the expanding va sculature. VEGF was predominantly produced in tissues that acquire new capillary networks (theca layers, lutein cells, endometrial stroma, a nd the maternal decidua, respectively). VEGF-binding activity, on the other hand, was found on endothelial cells of both quiescent and proli ferating blood vessels. These findings are consistent with a role for VEGF in the targeting of angiogenic responses to specific areas. Using in situ hybridization, we show that VEGF is expressed in 10 different steroidogenic and / or steroid-responsive cell types (theca, cumulus, granulosa, lutein, oviductal epithelium, endometrial stroma, decidua, giant trophoblast cells, adrenal cortex, and Leydig cells). Furthermo re, in some cells upregulation of VEGF expression is concurrent with t he acquisition of steroidogenic activity, and expression in other cell types is restricted to a particular stage of the ovarian cycle. These findings suggest that expression of VEGF is hormonally regulated. We propose that excessive expression of VEGF during gonadotropin-induced ovulation may contribute to the development of ovarian hyperstimulatio n syndromes by virtue of the vascular permeabilization activity of thi s factor.