Allerkamp Hanna, Lehner Stefanie, Ekhlasi-Hundrieser Mahnaz, Detering Carsten, Pfarrer Christiane, Depka Prondzinski Mario von
Department of Fundamental and Clinical Research, Werlhof Institute, Hannover, Lower Saxony, Germany; Institute of Anatomy, University of Veterinary Medicine Hannover Foundation, Hannover, Lower Saxony, Germany;, Email:
Department of Fundamental and Clinical Research, Werlhof Institute, Hannover, Lower Saxony, Germany.
Comp Med. 2019 Oct 1;69(5):401-412. doi: 10.30802/AALAS-CM-19-000003. Epub 2019 Sep 16.
Von Willebrand disease (VWD), a blood coagulation disorder, is also known to cause angiodysplasia. Hitherto, no animal model has been found with angiodysplasia that can be studied in vivo. In addition, VWD patients tend to have a higher incidence of miscarriages for reasons unknown. Thus, we aimed to examine the influence of von Willebrand factor (VWF) on the female reproductive tract histology and the expression and distribution of angiogenic factors in a porcine model for VWD types 1 and 3. The disease-causing tandem duplication within the gene occurred naturally in these pigs, making them a rare and valuable model. Reproductive organs of 6 animals (2 of each mutant genotype and 2 wildtype (WT) animals) were harvested. Genotype plus phenotype were confirmed. Several angiogenic factors were chosen for possible connections to VWF and analyzed alongside VWF by immunohistochemistry and quantitative gene expression studies. VWD type 3 animals showed angiodysplasia in the uterus and shifting of integrin αβ₃ from the apical membrane of uterine epithelium to the cytoplasm accompanied by increased vascular endothelial growth factor ( expression. Varying staining patterns for angiopoietin (Ang)-2 were observed among the genotypes. As compared with WT, the ovaries of the VWD type 3 animals showed decreased gene expression of and increased gene expression of tyrosine kinase with immunoglobulin and epidermal growth factor homology domains with some differences in the ANG/TIE-system among the mutant genotypes. In conclusion, severely reduced VWF seems to evoke angiodysplasia in the porcine uterus. Varying distribution and expression of angiogenic factors suggest that this large animal model is promising for investigation of influence of VWF on angiogenesis in larger groups.
血管性血友病（VWD）是一种凝血障碍疾病，也已知会导致血管发育异常。迄今为止，尚未发现可在体内研究的患有血管发育异常的动物模型。此外，血管性血友病患者流产的发生率往往较高，原因不明。因此，我们旨在研究血管性血友病因子（VWF）对1型和3型血管性血友病猪模型雌性生殖道组织学以及血管生成因子表达和分布的影响。这些猪自然发生了该基因内的致病串联重复，使其成为一种罕见且有价值的模型。采集了6只动物（每种突变基因型2只和2只野生型（WT）动物）的生殖器官。确认了基因型和表型。选择了几种可能与VWF相关的血管生成因子，并通过免疫组织化学和定量基因表达研究与VWF一起进行分析。3型血管性血友病动物子宫出现血管发育异常，整合素αβ₃从子宫上皮顶端膜转移至细胞质，同时血管内皮生长因子（）表达增加。在各基因型中观察到血管生成素（Ang）-2的染色模式不同。与野生型相比，3型血管性血友病动物的卵巢显示基因表达降低，酪氨酸激酶与免疫球蛋白和表皮生长因子同源结构域的基因表达增加，突变基因型之间的ANG/TIE系统存在一些差异。总之，严重降低的VWF似乎会引发猪子宫的血管发育异常。血管生成因子的不同分布和表达表明，这种大型动物模型有望用于研究VWF对更大群体血管生成的影响。
