Influence of Dll4 via HIF-1α-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions.
Influence of Dll4 via HIF-1α-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions.
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DOI：
10.1371/journal.pone.0018481
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发表时间：
2011-04-19
期刊：
影响因子：
3.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Dong X;Wang YS;Dou GR;Hou HY;Shi YY;Zhang R;Ma K;Wu L;Yao LB;Cai Y;Zhang J
脉络膜新生血管(CNV)是多种脉络膜视网膜疾病常见的不可逆性视力损害的病理基础，其发病机制复杂，至今仍不完全清楚。最近的研究表明，作为Notch家族的配体之一，Delta样配体4(DLL4)可能参与了缺氧诱导因子-1α-血管内皮生长因子途径，从而调节新生血管的形成。但目前对DLL4/Notch信号对CNV血管生成的影响及其可能的机制还知之甚少。实时荧光定量RT-PCR法、Western blotting法检测缺氧RF/6A细胞中DLL4、血管内皮生长因子和缺氧诱导因子-1α的表达变化。免疫荧光染色、激光诱导的大鼠CNV模型和玻璃体内注射技术证实了这些分子在体外和体内的关系。采用RPE-RF/6A细胞共培养系统研究DLL4/Notch信号对CNV血管生成的影响。我们发现DLL4参与了CNV血管生成的低氧信号转导。共培养结果显示，在低氧环境中，DLL4表达增强可显著加快RPE细胞的增殖，增强RPE细胞的管形成能力，但抑制细胞在单层RPE细胞间的迁移和侵袭，而siRNA介导的DLL4沉默则产生相反的作用。使用伽马分泌酶抑制剂(GSI)对Notch信号的药理学干扰产生了与DLL4 siRNA相似但不完全相同的效果。此外，在表达DLL4的RF/6A细胞中，参与CNV血管生成的几个关键分子的表达也发生了变化。这些结果提示DLL4在新生血管生成中起重要作用，在缺氧条件下新生血管的形成过程中可能受缺氧诱导因子-1α和血管内皮生长因子的调节。靶向DLL4/Notch信号转导可能有助于进一步了解CNV血管生成的机制。
Choroidal neovascularization (CNV) is the common pathological basis of irreversible visual impairment encountered in a variety of chorioretinal diseases; the pathogenesis of its development is complicated and still imperfectly understood. Recent studies indicated that delta-like ligand 4 (Dll4), one of the Notch family ligands might participate in the HIF-1α-VEGF pathway to regulate CNV angiogenesis. But little is known about the influence and potential mechanism of Dll4/Notch signals on CNV angiogenesis. Real-time RT-PCR, Western blotting were used to analyze the expression alteration of Dll4, VEGF and HIF-1α in hypoxic RF/6A cells. Immunofluorescence staining, a laser-induced rat CNV model and intravitreal injection techniques were used to confirm the relationships among these molecules in vitro and in vivo. RPE-RF/6A cell co-culture systems were used to investigate the effects of Dll4/Notch signals on CNV angiogenesis. We found that the Dll4 was involved in hypoxia signaling in CNV angiogenesis. Results from the co-culture system showed that the enhancement of Dll4 expression in RF/6A cells led to the significantly faster proliferation and stronger tube forming ability, but inhibited cells migration and invasion across a monolayer of RPE cells in hypoxic environment, while siRNA-mediated Dll4 silencing caused the opposite effects. Pharmacological disruption of Notch signaling using gamma-secretase inhibitor (GSI) produced similar, but not identical effects, to that caused by the Dll4 siRNA. In addition, the expression of several key molecules involved in the angiogenesis of CNV was altered in RF/6A cells showing constitutively active Dll4 expression. These results suggest that Dll4 play an important role in CNV angiogenesis, which appears to be regulated by HIF-1α and VEGF during the progression of CNV under hypoxic conditions. Targeting Dll4/Notch signaling may facilitate further understanding of the mechanisms that underlie CNV angiogenesis.
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影响因子：
1.2
作者：
Hofmann, Jennifer J.;Iruela-Arispe, M. Luisa
通讯作者：
Iruela-Arispe, M. Luisa
影响因子：
64.5
作者：
Benedito, Rui;Roca, Cristina;Adams, Ralf H.
通讯作者：
Adams, Ralf H.
影响因子：
64.5
作者：
Kopan R;Ilagan MX
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Ilagan MX
影响因子：
3.9
作者：
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通讯作者：
Gerhardt, Holger
DOI：
10.1073/pnas.0611206104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Lobov, I. B.;Renard, R. A.;Wiegand, S. J.
通讯作者：
Wiegand, S. J.