Pellegrin Maxime, Bouzourène Karima, Poitry-Yamate Carole, Mlynarik Vladimir, Feihl François, Aubert Jean-François, Gruetter Rolf, Mazzolai Lucia
Division of Angiology, University Hospital of Lausanne, Lausanne, Switzerland.
Centre d'Imagerie Biomédicale, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Physiol Rep. 2014 Feb 25;2(2):e00234. doi: 10.1002/phy2.234. eCollection 2014 Feb 1.
Peripheral arterial disease (PAD) is a common disease with increasing prevalence, presenting with impaired walking ability affecting patient's quality of life. PAD epidemiology is known, however, mechanisms underlying functional muscle impairment remain unclear. Using a mouse PAD model, aim of this study was to assess muscle adaptive responses during early (1 week) and late (5 weeks) disease stages. Unilateral hindlimb ischemia was induced in ApoE(-/-) mice by iliac artery ligation. Ischemic limb perfusion and oxygenation (Laser Doppler imaging, transcutaneous oxygen pressure assessments) significantly decreased during early and late stage compared to pre-ischemia, however, values were significantly higher during late versus early phase. Number of arterioles and arteriogenesis-linked gene expression increased at later stage. Walking ability, evaluated by forced and voluntary walking tests, remained significantly decreased both at early and late phase without any significant improvement. Muscle glucose uptake ([18F]fluorodeoxyglucose positron emission tomography) significantly increased during early ischemia decreasing at later stage. Gene expression analysis showed significant shift in muscle M1/M2 macrophages and Th1/Th2 T cells balance toward pro-inflammatory phenotype during early ischemia; later, inflammatory state returned to neutrality. Muscular M1/M2 shift inhibition by a statin prevented impaired walking ability in early ischemia. High-energy phosphate metabolism remained unchanged (31-Phosphorus magnetic resonance spectroscopy). Results show that rapid transient muscular inflammation contributes to impaired walking capacity while increased glucose uptake may be a compensatory mechanisms preserving immediate limb viability during early ischemia in a mouse PAD model. With time, increased ischemic limb perfusion and oxygenation assure muscle viability although not sufficiently to improve walking impairment. Subsequent decreased muscle glucose uptake may partly contribute to chronic walking impairment. Early inflammation inhibition and/or late muscle glucose impairment prevention are promising strategies for PAD management.
外周动脉疾病（PAD）是一种常见疾病，患病率呈上升趋势，其表现为步行能力受损，影响患者生活质量。虽然PAD的流行病学情况已知，但功能性肌肉损伤的潜在机制仍不清楚。本研究利用小鼠PAD模型，旨在评估疾病早期（1周）和晚期（5周）的肌肉适应性反应。通过结扎髂动脉在载脂蛋白E基因敲除（ApoE(-/-)）小鼠中诱导单侧后肢缺血。与缺血前相比，早期和晚期缺血肢体的灌注和氧合（激光多普勒成像、经皮氧分压评估）均显著降低，但晚期的值明显高于早期。小动脉数量和与动脉生成相关的基因表达在后期增加。通过强制和自愿步行试验评估的步行能力在早期和晚期均显著下降，且无任何显著改善。肌肉葡萄糖摄取（[18F]氟脱氧葡萄糖正电子发射断层扫描）在早期缺血期间显著增加，在后期降低。基因表达分析显示，在早期缺血期间，肌肉M1/M2巨噬细胞和Th1/Th2 T细胞平衡显著向促炎表型转变；随后，炎症状态恢复到中性。他汀类药物抑制肌肉M1/M2转变可预防早期缺血时的步行能力受损。高能磷酸代谢保持不变（31-磷磁共振波谱）。结果表明，快速短暂的肌肉炎症导致步行能力受损，而葡萄糖摄取增加可能是一种补偿机制，在小鼠PAD模型的早期缺血期间维持肢体的即时存活能力。随着时间的推移，缺血肢体灌注和氧合增加可确保肌肉存活，尽管不足以改善步行障碍。随后肌肉葡萄糖摄取减少可能部分导致慢性步行障碍。早期炎症抑制和/或晚期肌肉葡萄糖损伤预防是PAD管理的有前景的策略。
