Department of Medicine, University of California, San Diego, CA, USA.
University Pompeu Fabra, Barcelona, Spain.
Exp Physiol. 2020 Dec;105(12):2168-2177. doi: 10.1113/EP088924. Epub 2020 Oct 14.
What is the central question of this study? Does vascular endothelial growth factor (VEGF) expressed by both endothelial cells and skeletal myofibres maintain the number of skeletal muscle capillaries and regulate endurance exercise? What is the main finding and its importance? VEGF expressed by both endothelial cells and skeletal myofibres is not essential for maintaining capillary number but does contribute to exercise performance.
Many chronic diseases lead to exercise intolerance, with loss of skeletal muscle capillaries. While many muscle cell types (myofibres, satellite cells, endothelial cells, macrophages and fibroblasts) express vascular endothelial growth factor (VEGF), most muscle VEGF is stored in myofibre vesicles which can release VEGF to signal VEGF receptor-expressing cells. VEGF gene ablation in myofibres or endothelial cells alone does not cause capillary regression. We hypothesized that simultaneously deleting the endothelial cell (EC) and skeletal myofibre (Skm) VEGF gene would cause capillary regression and impair exercise performance. This was tested in adult mice by simultaneous conditional deletion of the VEGF gene (Skm/EC-VEGF mice) through the use of VEGFLoxP, HSA-Cre-ER and PDGFb-iCre-ER transgenes. These double-deletion mice were compared to three control groups - WT, EC VEGF gene deletion alone and myofibre VEGF gene deletion alone. Three weeks after initiating gene deletion, Skm/EC-VEGF mice, but not SkmVEGF or EC-VEGF mice, reached exhaustion 40 min sooner than WT mice in treadmill tests (P = 0.002). WT, SkmVEGF and EC-VEGF , but not Skm/EC-VEGF , mice gained weight over the 3 weeks. Capillary density, fibre area and capillary: fibre ratio in soleus, plantaris, gastrocnemius and cardiac papillary muscle were similar across the groups. Phosphofructokinase and pyruvate dehydrogenase activities increased only in Skm/EC-VEGF mice. These data suggest that deletion of the VEGF gene simultaneously in endothelial cells and myofibres, while reducing treadmill endurance and despite compensatory augmentation of glycolysis, is not required for muscle capillary maintenance. Reduced endurance remains unexplained, but may possibly be related to a role for VEGF in controlling perfusion of contracting muscle.
本研究的核心问题是什么？内皮细胞和骨骼肌纤维表达的血管内皮生长因子（VEGF）是否维持骨骼肌毛细血管数量并调节耐力运动？主要发现及其重要性是什么？内皮细胞和骨骼肌纤维表达的 VEGF 对于维持毛细血管数量不是必需的，但有助于运动表现。
许多慢性疾病导致运动不耐受，导致骨骼肌毛细血管丧失。虽然许多肌细胞类型（肌纤维、卫星细胞、内皮细胞、巨噬细胞和成纤维细胞）表达血管内皮生长因子（VEGF），但大多数肌肉 VEGF 储存在肌纤维囊泡中，这些囊泡可以释放 VEGF 以信号 VEGF 受体表达细胞。单独敲除肌纤维或内皮细胞中的 VEGF 基因不会引起毛细血管退化。我们假设同时敲除内皮细胞（EC）和骨骼肌纤维（Skm）的 VEGF 基因会导致毛细血管退化并损害运动表现。这在成年小鼠中通过使用 VEGFLoxP、HSA-Cre-ER 和 PDGFb-iCre-ER 转基因同时条件性敲除 VEGF 基因（Skm/EC-VEGF 小鼠）进行了测试。这些双缺失小鼠与三组对照小鼠进行了比较——WT、单独敲除 EC 的 VEGF 基因和单独敲除肌纤维的 VEGF 基因。在开始基因缺失后 3 周，Skm/EC-VEGF 小鼠在跑步机测试中比 WT 小鼠早 40 分钟达到疲劳（P=0.002）。WT、SkmVEGF 和 EC-VEGF，但不是 Skm/EC-VEGF，小鼠在 3 周内体重增加。比目鱼肌、跖肌、腓肠肌和心脏乳头肌的毛细血管密度、纤维面积和毛细血管：纤维比在各组之间相似。磷酸果糖激酶和丙酮酸脱氢酶活性仅在 Skm/EC-VEGF 小鼠中增加。这些数据表明，内皮细胞和肌纤维中同时敲除 VEGF 基因，尽管降低了跑步机耐力，并且尽管糖酵解代偿性增加，但并不需要维持肌肉毛细血管。耐力降低仍未得到解释，但可能与 VEGF 在控制收缩肌肉灌注中的作用有关。
