Expression of angiogenic factors in the uteroplacental unit is altered at time of placentation in a porcine model of von Willebrand disease type 1

Von Willebrand disease (VWD) affects blood coagulation and correlates with angiodysplasia. Data on VWD-affected women point to slightly increased miscarriage rates. We aimed to investigate the impact of VWD on angiogenesis in the uteroplacental unit of pregnant pigs of a model of VWD type 1 (T1). Uteri, placentae, and embryos were harvested at time of placentation (day 29 to 31) from four sows (two wildtype (WT) and two heterozygous for a von Willebrand factor (VWF) mutation diagnosed with T1). T1 sows were bred to a T1 boar creating embryos of three different genotypes: WT, T1 or homozygous for the VWF mutation corresponding with VWD type 3 (T3). Uteroplacental tissues were examined histologically. Embryos were genotyped. Gene expression of angiogenic factors possibly related to VWF was determined by quantitative real-time PCR. Corresponding protein expression was analyzed by immunohistochemistry. Genotyping revealed 35.3% WT, 52.9% T1 and 5.9% T3 embryos (5.9% not classified confidently). No histological alterations were found. Gene expression of VEGF was significantly increased in T1 placentae while expression of ANG1, ANG2, TIE2, and ITGB3 was significantly reduced, confirmed on protein level for different cell types. TIE2/TIE1 ratios were significantly lower in T1 placentae. Distribution of embryo genotypes indicates selection favoring the WT. Significant expression differences of angiogenic factors in placentae suggest influence of VWF on these factors during placentation, although angiodysplasia was not observed. The alterations concerning VEGF/VEGFR-2 signaling, integrin expression and the ANG/TIE system may influence angiogenesis and vascular adaptation during placentation and thus the overall outcome of pregnancy.