Dll4-Notch1 signaling but not VEGF-A is essential for hyperoxia induced vessel regression in retina.
Dll4-Notch1 signaling but not VEGF-A is essential for hyperoxia induced vessel regression in retina.
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Dll4-Notch1 信号而非 VEGF-A 对高氧诱导视网膜血管退化至关重要
DOI：
10.1016/j.bbrc.2018.11.051
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发表时间：
2018-12-09
影响因子：
3.1
通讯作者：
Pang J
中科院分区：
文献类型：
--
作者：
Zhu G;Lin Y;Liu H;Jiang D;Singh S;Li X;Yu Z;Fan L;Wang S;Rhen J;Li W;Xu Y;Ge J;Pang J
众所周知，血管内皮生长因子A（VEGF-A）mRNA的减少在高氧诱导的视网膜血管退行中发挥着重要作用。然而，这一概念受到越来越多新证据的挑战。此外，VEGF-A强烈增强Dll 4表达，并且Dll 4-Notch信号传导的抑制导致过度的出芽血管生成。最近，研究表明Dll 4-Notch 1信号转导的失活减少了高氧诱导的血管退化。目前尚不清楚萌芽血管生成是否有助于保护作用，需要进一步研究。为了确定VEGF-A和Dll 4-Notch 1信号在视网膜中高氧诱导的血管退化中的作用，我们使用出生后第5天（P5）- P7的小鼠。高氧诱导大量的中央血管丛，但不是在血管生成丛的血管退化，并没有影响萌芽血管生成。免疫组化显示，VEGF-A显着抑制高氧暴露后，在血管生成的前部区域，但在正常氧和高氧处理的视网膜的中心区域检测不到。相反，Notch配体Delta样4（Dll 4）和Notch 1胞内结构域（N1-ICD）的表达在视网膜中央的毛细血管中受到抑制，但在高氧处理后的血管生成丛中相当。此外，给予Dll 4中和抗体或γ-分泌酶抑制剂DAPT显著加重了短时间高氧给药引起的血管退行性变。我们的数据表明，Dll 4-Notch 1信号通路的抑制，而不是VEGF-A表达下调负责高氧诱导的广泛血管退行。
It is well recognized that decreased vascular endothelial growth factor A (VEGF-A) mRNA plays an important role in retinal vessel regression induced by hyperoxia. However, this concept has been challenged by increasing new evidence. Furthermore, VEGF-A strongly enhances Dll4 expression and inhibition of Dll4-Notch signaling leads to excessive sprouting angiogenesis. Recently, it is shown that inactivation of Dll4-Notch1 signaling reduce hyperoxia induced vessel regression. It is unknown whether sprouting angiogenesis contributes to the protective effect or not and further investigations are needed. Moreover, the expression of Dll4 or Notch1 activation in the regressing plexus remains elucidated.To determine the role of VEGF-A and Dll4-Notch1 signaling in hyperoxia induced vascular regression in the retina, we used mice at postnatal day 5 (P5) - P7. Hyperoxia induced massive vascular regression in the central plexus but not in the angiogenic plexus and had no effect on sprouting angiogenesis. Immunostaining showed that VEGF-A was significantly repressed in the angiogenic front region after hyperoxia exposure but not detectable in the central area of both normoxia and hyperoxia treated retinas. In contrast, Notch ligand Delta-like 4 (Dll4) and Notch1 intracellular domain (N1-ICD) expression were inhibited in the regressing capillaries of central retina but comparable in the angiogenic plexus after high oxygen treatment. Moreover, administration of Dll4 neutralizing antibody or γ-Secretase inhibitor DAPT significantly aggravated vessel regression induced by short-time hyperoxia administration. Our data show that repressed Dll4-Notch1 signaling pathway but not downregulation of VEGF-A expression are responsible for hyperoxia induced pervasive vessel regression.
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影响因子：
64.8
作者：
Polacheck WJ;Kutys ML;Yang J;Eyckmans J;Wu Y;Vasavada H;Hirschi KK;Chen CS
通讯作者：
Chen CS
影响因子：
24.3
作者：
Dabral, Swati;Tian, Xia;Schermuly, Ralph Theo
通讯作者：
Schermuly, Ralph Theo
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：
9.8
作者：
Fruttiger, Marcus
通讯作者：
Fruttiger, Marcus
影响因子：
4.6
作者：
Ehling, Manuel;Adams, Susanne;Adams, Ralf H.
通讯作者：
Adams, Ralf H.