Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice
Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice
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DOI：
10.1172/jci34882
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发表时间：
2008-07-01
影响因子：
15.9
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Kubota, Yoshiaki;Hirashima, Masanori;Suda, Toshio
为了满足组织对氧气的需求，毛细血管必须适当地分布，不能过多或不足。在这个过程中，众所周知，组织氧浓度通过缺氧诱导的级联反应决定毛细血管密度，其中HIF和VEGF起关键作用。然而，一些额外的机制调节这级联建议参与精确的毛细血管网络的形成。在这里，我们发现白血病抑制因子（LIF）主要表达在发育中的内皮细胞，而其受体表达在周围细胞，如视网膜星形胶质细胞。Lif（-/-）小鼠视网膜显示微血管密度增加，伴随着持续的尖端细胞活性，由于血管化区域星形胶质细胞VEGF表达增加。在氧诱导的视网膜病变模型中，Lif（-/-）小鼠抵抗了高氧损伤，然而它们的新生血管簇数量却增加了。在体外研究中，LIF抑制缺氧诱导的VEGF表达和增殖培养的星形胶质细胞。Lif（-/-）小鼠在视网膜外的各种组织中也表现出类似的微血管密度增加和VEGF上调。总之，这些研究结果表明，组织和推进血管系统沟通，以确保充分的血管化使用LIF以及氧气，这表明一种新的策略，抗血管生成治疗人类疾病，如糖尿病视网膜病变和癌症。
To meet tissue requirements for oxygen, capillaries must be properly distributed without excess or shortage. In this process, tissue oxygen concentration is well known to determine capillary density via the hypoxia-induced cascade, in which HIFs and VEGF play key roles. However, some additional mechanisms modulating this cascade are suggested to be involved in precise capillary network formation. Here, we showed that leukemia inhibitory factor (LIF) was predominantly expressed in developing endothelium, while its receptor was expressed in surrounding cells such as retinal astrocytes. The retinas of Lif(-/-) mice displayed increased microvessel density accompanied by sustained tip cell activity, due to increased VEGF expression by astrocytes in the vascularized area. Lif(-/-) mice resisted hyperoxygen insult in the oxygen-induced retinopathy model, whereas they paradoxically had increased numbers of neovascular tufts. In an in vitro study, LIF inhibited hypoxia-induced VEGF expression and proliferation in cultured astrocytes. Lif(-/-) mice also exhibited similarly increased microvessel density and upregulated VEGF in various tissues outside the retina. Together, these findings suggest that tissues and advancing vasculature communicate to ensure adequate vascularization using LIF as well as oxygen, which suggests a new strategy for antiangiogenic therapy in human diseases such as diabetic retinopathy and cancer.