PEDF inhibits VEGF- and EPO- induced angiogenesis in retinal endothelial cells through interruption of PI3K/Akt phosphorylation (Retracted article. See vol. 14, pg. 407, 2011)
PEDF inhibits VEGF- and EPO- induced angiogenesis in retinal endothelial cells through interruption of PI3K/Akt phosphorylation (Retracted article. See vol. 14, pg. 407, 2011)
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DOI：
10.1007/s10456-009-9153-5
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发表时间：
2009-12-01
期刊：
影响因子：
9.8
通讯作者：
Gurunathan, Sangiliyandi
中科院分区：
文献类型：
--
作者：
Elayappan, Banumathi;Ravinarayannan, Haribalaganesh;Gurunathan, Sangiliyandi
糖尿病视网膜血管生成可导致世界范围内劳动年龄人群的视力损害甚至不可逆失明。增殖性糖尿病视网膜病变（PDR）的主要病理特征是缺氧，以及血管内皮生长因子（VEGF）和促红细胞生成素（Epo）等生长因子的过量产生。这导致视网膜内皮细胞（RECs）的病理性增殖，导致新血管形成（血管生成）。抑制血管生成是治疗PDR和其他视网膜新生血管疾病的一种很有前途的策略。色素上皮衍生因子（PEDF）是由视网膜色素上皮分泌的一种50 kda的蛋白，通过多种方式抑制眼睛新生血管的生长，其机制尚不明确。在这里，我们研究了PEDF通过PI3K/Akt通路抑制VEGF和epo诱导的rec血管生成效应的可能机制。PEDF通过激活caspase-3和DNA断裂诱导RECs细胞凋亡。我们发现VEGF或Epo的细胞存活率呈剂量依赖性增加，而PEDF的存在则减弱。此外，PEDF与PI3K/Akt抑制剂一样，在VEGF存在下显著（P < 0.05）抑制RECs的迁移和体外管形成。有趣的是，PEDF有效地消除了vegf介导的PI3K/Akt磷酸化。进一步研究表明，PEDF可以通过破坏PI3K/Akt信号通路抑制VEGF和epo诱导的血管生成。
Retinal angiogenesis in diabetes may lead to visual impairment and even irreversible blindness in people of working age group worldwide. The main pathological feature of proliferative diabetic retinopathy (PDR) is hypoxia, and overproduction of growth factors like vascular endothelial growth factor (VEGF) and erythropoietin (Epo). This results in pathological proliferation of retinal endothelial cells (RECs), leading to new vessel formation (angiogenesis). Inhibition of angiogenesis is a promising strategy for treatment of PDR and other retinal neovascular disorders. Pigment epithelium-derived factor (PEDF), a 50-kDa protein secreted by retinal pigment epithelium, inhibits the growth of new blood vessel induced in the eye in a variety of ways with a yet elusive mechanism. Here, we investigated the possible mechanism by which PEDF inhibits VEGF- and Epo-induced angiogenic effects in RECs is mediated through PI3K/Akt pathway. PEDF treatment induced the apoptosis in RECs by activating caspase-3 and DNA fragmentation. We found a dose-dependent increase in cell survival with VEGF or Epo, which was attenuated in the presence of PEDF. In addition, PEDF significantly (P < 0.05) inhibited migration and in vitro tube formation in RECs in the presence of VEGF as like PI3K/Akt inhibitor. Of interest, PEDF effectively abrogated VEGF-mediated phosphorylation of PI3K/Akt. Further studies using RECs transfected with constitutively active and dominant-negative forms of Akt suggest that PEDF could inhibit VEGF- and also Epo-induced angiogenesis by disruption of PI3K/Akt signaling.