A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus

A key mechanism underlying physiological angiogenesis of the human endometrium is its ability to regenerate the vascular capillary network and to perform vascular remodeling (i.e., development of spiral arteries). Vascular endothelial growth factor (VEGF) is associated with angiogenesis and capillary permeability in this tissue. VEGF is expressed as several spliced variants, its main human isoforms contain 121 and 165 aa; 17beta-estradiol (E-2) increases endometrial VEGF, possibly in all isoforms. Here we show that progesterone (P) selectively increases the expression of the VEGF(189) (V-189) isoform in the human uterus. V-189 is identified in the conditioned medium of stromal cells treated with E-2 + P; its presence in this in vitro model of decidual stromal cells is detected after 6-8 days, using ELISA, and after 8-10 days, using Western blot analysis with different antibodies, including one specific for V-189. The secretion pattern Of V-189 parallels that of the decidual protein IGFBP-1. V-189 is secreted as a native isoform, as compared with the migration of recombinant V-189 by SDS/PAGE. In situ hybridization and immunocytochemistry, performed on the same biopsies, suggest that decidual cells express V-189 during the mid-late secretory phase of the menstrual cycle and early gestation. Finally, using an in vivo permeability assay, we show that native V-189 increases capillary permeability. These observations demonstrate that P regulates V-189 expression in decidual cells, which could have important implications for understanding uterine vascular remodeling and implantation, and may be relevant in a range of disease states such as edema and irregular bleeding.