Cell and molecular mechanisms of insulin-induced angiogenesis.
Cell and molecular mechanisms of insulin-induced angiogenesis.
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DOI：
10.1111/j.1582-4934.2008.00555.x
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发表时间：
2009-11
影响因子：
5.3
通讯作者：
Martins-Green M
中科院分区：
文献类型：
--
作者：
Liu Y;Petreaca M;Martins-Green M
血管生成，即从已有血管发展出新血管，是伤口愈合过程中肉芽组织形成的关键过程。新血管的适当发育，沿着它们随后的成熟和分化，为功能性伤口新生血管系统建立了基础。我们在体内进行了研究，并在体外使用了各种细胞和分子方法，以表明胰岛素刺激血管生成，并阐明这种蛋白质刺激微血管发育的信号转导机制。注射胰岛素的小鼠皮肤显示出更长的血管，分支更多，沿着相关的α-平滑肌肌动蛋白表达细胞数量增加，表明新血管的适当分化和成熟。我们还发现胰岛素刺激人微血管内皮细胞迁移和管形成，并且这些作用独立于VEGF/VEGFR信号传导而发生，但依赖于胰岛素受体本身。下游信号通路涉及PI 3 K、Akt、固醇调节元件结合蛋白1（SREBP-1）和Rac 1;抑制这些通路导致内皮细胞迁移和管形成的消除，并显著减少微血管的发育。我们的研究结果强烈表明，胰岛素是治疗缺血性伤口和其他血管发育受损的疾病的良好候选药物。
Angiogenesis, the development of new blood vessel from pre-existing vessels, is a key process in the formation of the granulation tissue during wound healing. The appropriate development of new blood vessels, along with their subsequent maturation and differentiation, establishes the foundation for functional wound neovasculature. We performed studies in vivo and used a variety of cellular and molecular approaches in vitro to show that insulin stimulates angiogenesis and to elucidate the signalling mechanisms by which this protein stimulates microvessel development. Mice skin injected with insulin shows longer vessels with more branches, along with increased numbers of associated α-smooth muscle actin-expressing cells, suggesting the appropriate differentiation and maturation of the new vessels. We also found that insulin stimulates human microvascular endothelial cell migration and tube formation, and that these effects occur independently of VEGF/VEGFR signalling, but are dependent upon the insulin receptor itself. Downstream signalling pathways involve PI3K, Akt, sterol regulatory element-binding protein 1 (SREBP-1) and Rac1; inhibition of these pathways results in elimination of endothelial cell migration and tube formation and significantly decreases the development of microvessels. Our findings strongly suggest that insulin is a good candidate for the treatment of ischaemic wounds and other conditions in which blood vessel development is impaired.