ANGIOGENIC GROWTH FACTORS IN EXERCISING SKELETAL MUSCLE

运动刺激骨骼肌血管生成。毛细血管的增加改善了外周动脉功能不全(PAI)患者的肌肉功能和生活质量。因此，运动训练或促血管生成药物治疗(如果运动禁忌)可能对这些患者有帮助。然而，参与骨骼肌血管生成的生长因子、受体和信号通路还没有得到很好的描述。因此，这些研究将针对三个特定的目标：1)表征运动训练期间正常大鼠和后肢缺血大鼠红白腓肠肌血管生长因子含量和表达变化的时程；2)表征运动训练期间正常大鼠和后肢缺血大鼠红白腓肠肌血管生长因子受体含量和表达变化的时程；3)确定运动刺激血管生成是否需要发挥作用的一氧化氮信号通路或血管生成素/Tie-2系统。这些研究将利用股动脉结扎的大鼠，这是PAI的一种模型。大鼠将遵循一种已知的刺激血管生成的跑步机运动计划。对于特定的目标1和2，生长因子(血管内皮生长因子、碱性成纤维细胞生长因子、血管生成素-1和血管生成素-2)及其受体的水平将在血管扩张的初始阶段(28天)进行评估，并与毛细血管生长相关。对于特定的目标3，一氧化氮合酶或Tie-2(血管生成素受体)抑制对毛细血管生长和细胞增殖的影响将在大约2周的运动后进行评估。这些研究将促进对骨骼肌血管生成的了解，并可能建议PAI患者的治疗方法。

Exercise stimulates angiogenesis in skeletal muscle. The increased capillarity improves muscle function and quality of life in patients with peripheral arterial insufficiency (PAI). Thus, either exercise training or proangiogenic drug therapies (if exercise is contraindicated) could be helpful to these patients. However, the growth factors, receptors, and signaling pathways involved in skeletal muscle angiogenesis are not well characterized. Therefore, these studies will address three Specific Aims: 1) to characterize the time course of alterations in the content and expression of angiogenic growth factors in red and white gastrocnemius muscle of both normal rats and rats with hindlimb ischemia during an exercise training program; 2) to characterize the time course of alterations in the content and expression of receptors for angiogenic growth factors in red and white gastrocnemius muscle of both normal rats and rats with hindlimb ischemia during an exercise training program; and 3) to determine whether a functioning nitric oxide signaling pathway or the angiopoietin/Tie-2 system is essential for exercise- stimulated angiogenesis. These studies will utilize femorally- ligated rats, a model of PAI. Rats will follow a treadmill exercise program known to stimulate angiogenesis. For Specific Aims 1 and 2, levels of growth factors (VEGF, bFGF, angiopoietin- 1, and angiopoietin-2) and their receptors will be assessed over the initial period of vascular expansion (28 d) and correlated with capillary growth. For Specific Aim 3, the effect of nitric oxide synthase or Tie-2 (angiopoietin receptor) inhibition on capillary growth and cell proliferation will be evaluated following approximately 2 w of exercise. These studies will advance understanding of skeletal muscle angiogenesis and may suggest treatments for patients with PAI.