Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.
Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Thromb Haemost. 2018 Jan;118(1):152-160. doi: 10.1160/TH17-06-0397. Epub 2018 Jan 5.
Inhibition of von Willebrand factor (VWF) expression in endothelial cells results in enhanced, possible dysfunctional angiogenesis, consistent with observations of severe gastrointestinal bleedings caused by vascular malformations in patients with von Willebrand disease (VWD). VWF is stored in endothelial Weibel-Palade bodies (WPB) with several other mediators of angiogenesis, like angiopoietin-2, osteoprotegerin and galectin-3. Increased release of angiopoietin-2 has been observed in medium of endothelial cells lacking VWF, but data on circulating levels of angiogenic factors in patients with VWD are lacking. The aim of this study was therefore to investigate plasma levels of angiogenic factors in patients with various types of VWD to obtain more insight into the pathogenesis of vascular malformations in these patients. We hypothesized that VWF deficiency leads to increased circulating levels of other WPB components. We therefore measured plasma levels of the WPB components angiopoietin-2, osteoprotegerin and galectin-3 as well as two other angiogenic factors (angiopoietin-1 and vascular endothelial growth factor [VEGF]) that are not stored within WPB. We observed that various angiogenic mediators are significantly different between types of VWD patients. Type 2A VWD patients had higher angiopoietin-1 levels compared with type 2B patients. Patients who have increased VWF clearance had higher angiopoietin-2 levels, whereas patients who have impaired VWF synthesis had higher galectin-3 levels. VEGF levels were negatively associated with VWF levels as type 3 VWD patients had the highest VEGF levels. However, complete VWF deficiency did not lead to increased circulating levels of other WPB components.
在内皮细胞中抑制血管性血友病因子（VWF）的表达会导致增强的、可能功能失调的血管生成，这与血管性血友病（VWD）患者血管畸形引起严重胃肠道出血的观察结果一致。VWF 与几种其他血管生成介质一起储存在内皮细胞的 Weibel-Palade 小体（WPB）中，如血管生成素-2、骨保护素和半乳糖凝集素-3。在缺乏 VWF 的内皮细胞的培养基中观察到血管生成素-2的释放增加，但缺乏 VWD 患者循环中血管生成因子的水平的数据。因此，本研究的目的是研究不同类型 VWD 患者的血浆血管生成因子水平，以更深入地了解这些患者血管畸形的发病机制。我们假设 VWF 缺乏会导致其他 WPB 成分的循环水平增加。因此，我们测量了 WPB 成分血管生成素-2、骨保护素和半乳糖凝集素-3以及另外两种不在 WPB 中储存的血管生成因子（血管生成素-1 和血管内皮生长因子[VEGF]）的血浆水平。我们观察到，各种血管生成介质在 VWD 患者的类型之间存在显著差异。2A 型 VWD 患者的血管生成素-1 水平高于 2B 型患者。VWF 清除增加的患者血管生成素-2 水平较高，而 VWF 合成受损的患者半乳糖凝集素-3 水平较高。VEGF 水平与 VWF 水平呈负相关，因为 3 型 VWD 患者的 VEGF 水平最高。然而，完全的 VWF 缺乏并没有导致其他 WPB 成分的循环水平增加。
