Epac1 inhibition ameliorates pathological angiogenesis through coordinated activation of Notch and suppression of VEGF signaling
Epac1 inhibition ameliorates pathological angiogenesis through coordinated activation of Notch and suppression of VEGF signaling
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DOI：
10.1126/sciadv.aay3566
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发表时间：
2020-01-01
期刊：
影响因子：
13.6
通讯作者：
Cheng, Xiaodong
中科院分区：
文献类型：
--
作者：
Liu, Hua;Mei, Fang C.;Cheng, Xiaodong
在这项研究中，我们研究了Epac 1在病理性血管生成中的作用及其作为治疗血管增生性疾病的新靶点的潜力。Epac 1基因缺失改善了氧诱导视网膜病变（OIR）和颈动脉结扎小鼠模型中的病理性血管生成。此外，Epac 1的基因缺失或药理学抑制抑制了离体主动脉环外植体的微血管出芽。机制研究表明Epac 1是一种以前未被发现的γ-分泌酶/ Notch信号通路抑制剂，通过与γ-分泌酶相互作用，调节其细胞内运输，同时增强血管内皮生长因子信号，促进病理性血管生成。Epac特异性抑制剂的药理学给药抑制了野生型小鼠中OIR诱导的新生血管形成，重现了Epac 1基因敲除的表型。我们的研究结果表明，Epac 1信号是至关重要的病理性血管生成的进展，但不是生理性血管生成，新开发的Epac特异性抑制剂是有效的，在打击增殖性视网膜病变。
In this study, we investigated the roles of Epac1 in pathological angiogenesis and its potential as a novel therapeutic target for the treatment of vasoproliferative diseases. Genetic deletion of Epac1 ameliorated pathological angiogenesis in mouse models of oxygen-induced retinopathy (OIR) and carotid artery ligation. Moreover, genetic deletion or pharmacological inhibition of Epac1 suppressed microvessel sprouting from ex vivo aortic ring explants. Mechanistic studies revealed that Epac1 acted as a previously unidentified inhibitor of the gamma-secretase/ Notch signaling pathway via interacting with gamma-secretase and regulating its intracellular trafficking while enhancing vascular endothelial growth factor signaling to promote pathological angiogenesis. Pharmacological administration of an Epac-specific inhibitor suppressed OIR-induced neovascularization in wild-type mice, recapitulating the phenotype of genetic Epac1 knockout. Our results demonstrate that Epac1 signaling is critical for the progression of pathological angiogenesis but not for physiological angiogenesis and that the newly developed Epac-specific inhibitors are effective in combating proliferative retinopathy.