Baur Carolin, Geml Amanda, Wimmer Kira-Sofie, Heim Franziska, Holschbach Anja, Elbs Katharina, Rohrmoser Michael R, van den Heuvel Dominic, Bauer Alexander T, Schneider Stefan W, Merkus Daphne, Deindl Elisabeth
Institute of Surgical Research, Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
Int J Mol Sci. 2025 Sep 19;26(18):9137. doi: 10.3390/ijms26189137.
Peripheral artery disease is a common manifestation of atherosclerosis, characterized by insufficient tissue perfusion and chronic ischemia. Arteriogenesis and angiogenesis are essential endogenous mechanisms to restore blood flow and limit ischemic injury. The metalloprotease ADAMTS13, known for cleaving ultra-large von Willebrand factor, has been implicated in thrombotic and inflammatory regulation. However, its role in ischemic vascular remodeling remains unclear. Using a murine hind limb ischemia model, we investigated the effect of ADAMTS13 deficiency on arteriogenesis and angiogenesis by comparing male ADAMTS13 and wild-type control mice. Perfusion recovery, vascular cell proliferation, immune cell infiltration, and thrombotic activity were evaluated using laser Doppler measurements, immunohistochemical analysis of adductor and gastrocnemius muscle tissues, and in vivo microscopy. ADAMTS13 deficiency did not impair perfusion recovery, collateral artery growth, or capillarization. While platelet adhesion was slightly increased in ADAMTS13 mice, no thrombotic occlusions were observed. Inflammatory responses, including macrophage and neutrophil infiltration as well as macrophage polarization, were largely unaffected. Despite previous in vitro evidence indicating an angiogenic role for ADAMTS13, its absence did not compromise angiogenesis in vivo. Our findings suggest that ADAMTS13 does not play a critical role in ischemia-related angiogenesis and arteriogenesis under sterile conditions and may be relevant only in contexts involving acute and sufficiently strong thromboinflammatory stimuli.
外周动脉疾病是动脉粥样硬化的常见表现，其特征为组织灌注不足和慢性缺血。动脉生成和血管生成是恢复血流并限制缺血性损伤的重要内源性机制。金属蛋白酶ADAMTS13以切割超大血管性血友病因子而闻名，已被证明与血栓形成和炎症调节有关。然而，其在缺血性血管重塑中的作用仍不清楚。我们使用小鼠后肢缺血模型，通过比较雄性ADAMTS13基因缺陷小鼠和野生型对照小鼠，研究了ADAMTS13缺乏对动脉生成和血管生成的影响。使用激光多普勒测量、内收肌和腓肠肌组织的免疫组织化学分析以及体内显微镜检查来评估灌注恢复、血管细胞增殖、免疫细胞浸润和血栓形成活性。ADAMTS13缺乏并未损害灌注恢复、侧支动脉生长或毛细血管化。虽然ADAMTS13基因缺陷小鼠的血小板黏附略有增加，但未观察到血栓闭塞。包括巨噬细胞和中性粒细胞浸润以及巨噬细胞极化在内的炎症反应在很大程度上未受影响。尽管先前的体外证据表明ADAMTS13具有促血管生成作用，但其缺失并未损害体内血管生成。我们的研究结果表明，在无菌条件下，ADAMTS13在缺血相关的血管生成和动脉生成中不发挥关键作用，可能仅在涉及急性且足够强烈的血栓炎症刺激的情况下才相关。
