Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo
Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo
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DOI：
10.1038/nm1307
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发表时间：
2005-11-01
期刊：
影响因子：
82.9
通讯作者：
Byzova, TV
中科院分区：
文献类型：
--
作者：
Chen, JH;Somanath, PR;Byzova, TV
Akt激酶控制基本的细胞功能，包括增殖、凋亡、代谢和转录，并且已经被提出作为治疗血管生成依赖性病理学（例如癌症和缺血性损伤）的有希望的靶标。但它们在新生血管形成中的确切作用仍然难以捉摸。在这里，我们表明Akt 1是血管细胞中的主要亚型，并描述了Akt 1敲除对血管完整性和病理性血管生成的意想不到的后果。Akt 1（-/-）小鼠在三种不同的体内模型中的血管生成反应增强;这些增强的反应与血管成熟受损和血管通透性增加有关。尽管Akt 1（-/-）小鼠血管成熟受损可能归因于内皮型一氧化氮合酶（eNOS）活化减少，但血管通透性和血管生成的主要表型变化与两种内源性血管调节因子血小板反应蛋白1（TSP-1）和2（TSP-2）表达减少有关。TSP-1和TSP-2在移植野生型骨髓的小鼠中的重新表达纠正了Akt 1（-/-）小鼠中的血管生成异常。这些发现确立了Akt-血小板反应蛋白轴在血管生成中的关键作用。
Akt kinases control essential cellular functions, including proliferation, apoptosis, metabolism and transcription, and have been proposed as promising targets for treatment of angiogenesis-dependent pathologies, such as cancer and ischemic injury. But their precise roles in neovascularization remain elusive. Here we show that Akt1 is the predominant isoform in vascular cells and describe the unexpected consequences of Akt1 knockout on vascular integrity and pathological angiogenesis. Angiogenic responses in three distinct in vivo models were enhanced in Akt1(-/-) mice; these enhanced responses were associated with impairment of blood vessel maturation and increased vascular permeability. Although impaired vascular maturation in Akt1(-/-) mice may be attributed to reduced activation of endothelial nitric oxide synthase ( eNOS), the major phenotypic changes in vascular permeability and angiogenesis were linked to reduced expression of two endogenous vascular regulators, thrombospondins 1 ( TSP-1) and 2 ( TSP-2). Re-expression of TSP-1 and TSP-2 in mice transplanted with wild-type bone marrow corrected the angiogenic abnormalities in Akt1(-/-) mice. These findings establish a crucial role of an Akt-thrombospondin axis in angiogenesis.