Gene Expression And Regulation Of Implantation By VEGF In Mouse Uterus

Uterus development during pre-implantation stage affects implantation process andembryo growth. Aberrant uterus development is associated with many human reproductivediseases. Among the factors regulating uterus development vascular remodeling promoters arecritical for uterus function and fertility. Vascular endothelial growth factor (VEGF), as one ofthe major members, has been found to be important in endothelial cell growth and bloodvessel development, as well as in non-endothelial cells. VEGF mediation in reproduction hasbeen broadly studied, but VEGF-induced transcriptional machinery during implantationwindow has not been systematically studied. In this study, a genetically repressed VEGFmouse model was used to analyze uterus transcriptome at gestation2.5(G2.5) bySolexa/Illumina’s digital gene expression (DGE) system. A number of6500uterus-expressed,831uterus-specific and2398VEGF-regulated genes were identified. Gene ontology (GO)analysis indicated that genes actively involved in uterus development were members ofcollagen biosynthesis, cell proliferation and cell apoptosis. Uterus-specific genes wereenriched in activities of phosphatidyl inositol phosphate kinase, histone H3-K36demethylation and protein acetylation. Among VEGF-regulated genes, up-regulated wereassociated with RNA polymerase III activity while down-regulated were strongly related withmuscle development. Comparable numbers of antisense transcripts were identified.Expression levels of the antisense transcripts were found tightly correlated with their senseexpression levels, an indication of possibly non-specific transcripts generated around theactive promoters and enhancers. The antisense transcripts with exceptionally high or lowexpression levels and the antisense transcripts under VEGF regulation were also identified.These transcripts may be important candidates in regulation of uterus development. This studyprovides a global survey on genes and antisense transcripts regulated by VEGF in thepre-implantation stage. Results will contribute to further study the candidate genes andpathways in regulating implantation process and related diseases.VEGF repression leads to uterus malfunction and implantation failure. Digital geneexpression profiling has identified that genes actively involved in muscle development andcell matrix are significantly altered. H&E staining showed significantly morphologicalchanges in myometrium. Oxytocin receptors, known critical for muscle contraction duringlabor was significantly up regulated. Significant changes in cell apoptosis patterns wereaccompanied with these changes. These results indicate VEGF repression may affect normalmuscle development and function in the myometrium during the preimplantation stages. Themalfunction of muscle development may be a major factor that disrupted implantation processes. Oxytocin receptor, a critical factor in muscle contraction, may be partiallyresponsible for implantation failure.