Vascular phenotypes of Sox18/Vegfd double knockout mouse embryos. (A) Severity of the blood vascular phenotype of 12.5 dpc double mutant embryos in allelic series. Blood vascular phenotypes were increased depending on gene dosage loss of function. Blood vascular defects are characterized by generalized subcutaneous hemorrhage (black arrowheads). (B) Increased density of the blood vascular network in double knockout mice. Whole-mount immunofluorescence with the pan-endothelial cell marker ENDOMUCIN on embryonic skin at 14.5 dpc (a-d). At this stage, the blood vasculature in this area has developed and migrated toward the midline of the embryo. (e-h) Sox18/Vegfd double knock out displayed skin with increased vessel density (h) compared with Sox18^+/−, Vegfd^+/+ control embryos (e) and single knockout embryos (f-g). Dashed lines in panels a-d indicate the magnified area in panels e-h. Scale bar represents 400 μm.