Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation

The mechanism(s) by which localized vascular permeability and angiogenesis occur at the sites of implantation is not clearly understood. Vascular endo thelial growth factor (VEGF) is a key regulator of vasculogenesis during em bryogenesis and angiogenesis in adult tissues. VEGF is also a vascular perm eability factor. VEGF acts via two tyrosine kinase family receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). Recent evidence suggests that neuropilin-1 (NRP1), a receptor involved in neuronal cell guidance, is expressed in end othelial cells, binds to VEGF(165) and enhances the binding of VEGF(165) to VEGFR2. We examined the spatiotemporal expression of vegf isoforms, nrp1 a nd vegfr2 as well as their interactions in the periimplantation mouse uteru s. We observed that vegf(164) is the predominant isoform in the mouse uteru s. vegf(164) mRNA accumulation primarily occurred in epithelial cells on da ys 1 and 2 of pregnancy. On days 3 and 4, the subepithelial stroma in addit ion to epithelial cells exhibited accumulation of this mRNA. After the init ial attachment reaction on day 5, luminal epithelial and stromal cells imme diately surrounding the blastocyst exhibited distinct accumulation of vegf( 164) mRNA. On days 6-8, the accumulation of this mRNA occurred in both meso metrial and antimesometrial decidual cells. These results suggest that VEGF (164) is available in mediating vascular changes and angiogenesis in the ut erus during implantation and decidualization. This is consistent with coord inate expression of vegfr2, and nrp1, a VEGF(164)-specific receptor, in ute rine endothelial cells. Their expression was low during the first 2 days of pregnancy followed by increases thereafter. With the initiation and progre ssion of implantation (days 5-8), these genes were distinctly expressed in endothelial cells of the decidualizing stroma. Expression was more intense on days 6-8 at the mesometrial pole, the presumptive site of heightened ang iogenesis and placentation. However, the expression was absent in the avasc ular primary decidual zone immediately surrounding the implanting embryo. C rosslinking experiments showed that I-125-VEGF(165) binds to both NRP1 and VEGFR2 present in decidual endothelial cells. These results suggest that VE GF(164) NRP1 and VEGFR2 play a role in VEGF-induced vascular permeability a nd angiogenesis in the uterus required for implantation. genesis 26:213-224 , 2000. (C) 2000 Wiley-Liss, Inc.