Rowe Glenn C, Raghuram Srilatha, Jang Cholsoon, Nagy Janice A, Patten Ian S, Goyal Amrita, Chan Mun Chun, Liu Laura X, Jiang Aihua, Spokes Katherine C, Beeler David, Dvorak Harold, Aird William C, Arany Zolt
From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Circ Res. 2014 Aug 15;115(5):504-17. doi: 10.1161/CIRCRESAHA.115.303829. Epub 2014 Jul 9.
Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and peripheral artery disease but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle.
To test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle.
Here, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease.
PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.
骨骼肌血管生成的机制仍未得到充分理解。诱导生理性血管生成的努力有望用于治疗糖尿病微血管疾病和外周动脉疾病，但受到生理性血管生成复杂性以及老年和糖尿病患者血管生成反应不佳的阻碍。迄今为止，糖尿病血管疾病的最佳治疗方法仍是运动，但对于腿痛患者来说，这通常是一个具有挑战性的选择。过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）是一种强大的代谢调节因子，介导运动诱导的骨骼肌血管生成。
测试PGC-1α是否以及如何在成年骨骼肌中诱导功能性血管生成。
在此，我们表明肌肉中的PGC-1α能在成年、老年和糖尿病小鼠中强有力地诱导功能性血管生成。这一过程涉及多种细胞类型的协调作用，并导致形成有功能、无渗漏、结构合理的新生血管。这些发现与单独诱导血管内皮生长因子所引发的紊乱血管系统形成鲜明对比。生物信息学分析表明，PGC-1α诱导分泌性磷蛋白1的分泌并募集巨噬细胞。分泌性磷蛋白1刺激巨噬细胞分泌单核细胞趋化蛋白-1，进而激活相邻的内皮细胞、周细胞和平滑肌细胞。相比之下，在分泌性磷蛋白1基因敲除小鼠中诱导PGC-1α会导致毛细血管化不成熟和小动脉形成减弱。最后，将PGC-1α通过腺病毒载体导入年轻或年老及糖尿病小鼠的骨骼肌中，可改善外周动脉疾病小鼠后肢缺血模型中的血流恢复情况。
PGC-1α驱动骨骼肌中的功能性血管生成，可能重现了运动所引发的复杂生理性血管生成过程。
