Follistatin-like 1, a Secreted Muscle Protein, Promotes Endothelial Cell Function and Revascularization in Ischemic Tissue through a Nitric-oxide Synthase-dependent Mechanism
Follistatin-like 1, a Secreted Muscle Protein, Promotes Endothelial Cell Function and Revascularization in Ischemic Tissue through a Nitric-oxide Synthase-dependent Mechanism
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DOI：
10.1074/jbc.m803440200
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发表时间：
2008-11-21
影响因子：
4.8
通讯作者：
Walsh, Kenneth
中科院分区：
文献类型：
--
作者：
Ouchi, Noriyuki;Oshima, Yuichi;Walsh, Kenneth
肌源性Akt信号传导协调血管募集与正常组织生长。在这里，我们研究了卵泡抑素样1（Fstl 1）在调节内皮细胞功能和血管生长的肌肉中的作用。转基因Akt 1在骨骼肌中的过表达导致肌纤维生长，其与肌肉毛细血管密度的增加相耦合。肌源性Akt信号传导或缺血性后肢手术导致肌肉中Fstl 1的诱导和Fstl 1循环水平的增加。肌内注射表达Fstl 1的腺病毒载体（Ad-Fstl 1）可加速野生型小鼠缺血后肢的血流恢复并增加毛细血管密度，这与内皮型一氧化氮合酶（eNOS）在Ser-1179残基磷酸化的增加有关。在培养的内皮细胞中，Ad-Fstl 1刺激迁移和分化成网络结构，并抑制血清剥夺条件下的凋亡。这些细胞反应与Akt和eNOS的活化磷酸化有关。相反，转导显性阴性Akt或LY 294002阻断Fstl 1刺激的eNOS磷酸化和抑制Fstl 1刺激的细胞反应。用eNOS抑制剂N-G-硝基-L-精氨酸甲酯处理也减少Ad-Fstl 1诱导的内皮细胞迁移和分化。在eNOS缺失的小鼠中，Ad-Fstl 1对缺血肢体再灌注的刺激作用被取消。这些数据表明，Fstl 1是一种分泌的肌肉蛋白或肌因子，可以发挥促进内皮细胞功能的作用，并通过其激活Akt-eNOS信号传导的能力刺激血管再生，以响应缺血性损伤。
Myogenic Akt signaling coordinates blood vessel recruitment with normal tissue growth. Here, we investigated the role of Follistatin-like 1 (Fstl1) in the regulation of endothelial cell function and blood vessel growth in muscle. Transgenic Akt1 overexpression in skeletal muscle led to myofiber growth that was coupled to an increase in muscle capillary density. Myogenic Akt signaling or ischemic hind limb surgery led to the induction of Fstl1 in muscle and increased circulating levels of Fstl1. Intramuscular administration of an adenoviral vector expressing Fstl1 (Ad-Fstl1) accelerated flow recovery and increased capillary density in the ischemic hind limbs of wild-type mice, and this was associated with an increase in endothelial nitric oxide synthase (eNOS) phosphorylation at residue Ser-1179. In cultured endothelial cells, Ad-Fstl1 stimulated migration and differentiation into network structures and inhibited apoptosis under conditions of serum deprivation. These cell responses were associated with the activating phosphorylation of Akt and eNOS. Conversely, transduction with dominant-negative Akt or LY294002 blocked Fstl1-stimulated eNOS phosphorylation and inhibited Fstl1-stimulated cellular responses. Treatment with the eNOS inhibitor N-G-nitro-L-arginine methyl ester also reduced endothelial cell migration and differentiation induced by Ad-Fstl1. The stimulatory effect of Ad-Fstl1 on ischemic limb reperfusion was abolished in mice lacking eNOS. These data indicate that Fstl1 is a secreted muscle protein or myokine that can function to promote endothelial cell function and stimulates revascularization in response to ischemic insult through its ability to activate Akt-eNOS signaling.