Journal of Cardiovascular Translational Research ( IF 2.4 ) Pub Date : 2021-05-28 , DOI: 10.1007/s12265-021-10134-8 Juline N Deppen 1, 2 , Sydney C Ginn 1, 2 , Na Hee Kim 2 , Lanfang Wang 2 , Ronald J Voll 3 , Steven H Liang 4 , Mark M Goodman 3 , John N Oshinski 1, 3 , Rebecca D Levit 2
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Currently, there is no large animal model of sustained limb ischemia suitable for testing novel angiogenic therapeutics for peripheral artery disease (PAD) such as drugs, genes, materials, or cells. We created a large animal model suitable for efficacy assessment of these therapies by testing 3 swine hind limb ischemia (HLI) variations and quantifying vascular perfusion, muscle histology, and limb function. Ligation of the ipsilateral external and bilateral internal iliac arteries produced sustained gait dysfunction compared to isolated external iliac or unilateral external and internal iliac artery ligations. Hyperemia-dependent muscle perfusion deficits, depressed limb blood pressure, arteriogenesis, muscle atrophy, and microscopic myopathy were quantifiable in ischemic limbs 6 weeks post-ligation. Porcine mesenchymal stromal cells (MSCs) engineered to express a reporter gene were visualized post-administration via positron emission tomography (PET) in vivo. These results establish a preclinical platform enabling better optimization of PAD therapies, including cellular therapeutics, increasing bench-to-bedside translational success.
Graphical abstract
中文翻译：
可用于测试外周动脉疾病治疗的猪后肢缺血模型
目前，还没有适合测试外周动脉疾病（PAD）新型血管生成疗法（例如药物、基因、材料或细胞）的持续肢体缺血的大型动物模型。我们通过测试 3 种猪后肢缺血 (HLI) 变异并量化血管灌注、肌肉组织学和肢体功能，创建了适合评估这些疗法疗效的大型动物模型。与孤立的髂外动脉或单侧髂外和髂内动脉结扎相比，结扎同侧髂外动脉和双侧髂内动脉会产生持续的步态功能障碍。结扎后 6 周，缺血肢体中可量化充血依赖性肌肉灌注不足、肢体血压降低、动脉生成、肌肉萎缩和微观肌病。给药后，通过体内正电子发射断层扫描（PET）观察经过改造以表达报告基因的猪间充质基质细胞（MSC）。这些结果建立了一个临床前平台，可以更好地优化 PAD 疗法，包括细胞疗法，从而提高实验室到临床的转化成功率。
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