EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) AND VEGF-RECEPTOR MESSENGER RIBONUCLEIC-ACIDS IN THE PERIIMPLANTATION RABBIT UTERUS

The endometrial vasculature undergoes expansion during preimplantation stages and, even more prominently, after implantation. In addition to angiogenesis, vascular hyperpermeability accompanies the attachment a nd invasion of blastocysts into the uterine lining. Vascular endotheli al growth factor (VEGF) is an angiogenic factor expressed in mammalian uteri that also has potent activity in inducing vascular permeability . Rabbit uteri were examined using Northern and in situ hybridization to assess the temporal and spatial expression of VEGF and its receptor (Flk-1, Flt-1) mRNAs during the pre- and periimplantation periods (Da ys 0-8). Steady-state levels of VEGF mRNA were highest in endometrium at estrous and peri-implantation stages (Days 6-8). In situ hybridizat ion revealed a shift from uniform expression of VEGF transcripts throu ghout the uterus at estrus and Day 4, to an endometrial epithelial loc alization just before and during implantation. At implantation sites, a pronounced signal was present in the trophoblastic knobs, the syncyt ial aggregates that attach to and invade the endometrium. VEGF protein was detected by immunoblot analysis in peri-implantation-stage uteri but was below the limit of detection in estrous endometrium. VEGF rece ptor mRNAs were expressed in the uterus at all stages examined, with h igh levels of Flk-1 and Flt-1 at estrus and again just before implanta tion, 6-3/4 days pregnant. The high level just before implantation cor relates with in situ hybridization results showing a prominent, but tr ansient, signal for Flk-1 mRNA in the endometrial epithelium. During i mplantation, Flk-1 mRNA was associated with blood vessels of the endom etrial stroma. We conclude that VEGF is a candidate factor for the ind uction of vascular hyperpermeability at implantation in the rabbit and in the angiogenic process that follows.