Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia
Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia
复制标题
增强的Notch信号传导调节非生产性血运重建，以响应外周缺血小鼠模型中的一氧化氮-血管生成素信号传导
DOI：
10.1111/micc.12549
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发表时间：
2019
期刊：
影响因子：
2.4
通讯作者：
Machado M
中科院分区：
文献类型：
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作者：
Machado M
在大鼠肠系膜血管生成实验中，一氧化氮(NO)-血管生成素受体(TiE)-血管内皮生长因子(VEGF)信号的协同刺激可以诱导动脉粥样硬化。我们假设相同的外源性添加的生长因子的组合也会对动脉粥样硬化产生积极的影响，从而在单侧后肢缺血模型中恢复血流。结果与方法激光散斑成像评估，NO-TIE组比对照组小鼠血流恢复更快。缺血肌肉内的毛细血管密度没有变化，但微动脉密度在非束缚小鼠中更高。考虑到先前报道的血管内皮生长因子信号的有益作用，我们测试了没有Tie-VEGF的小鼠是否会显示出进一步的改善。令人惊讶的是，这些小鼠的恢复与对照组没有什么不同，小动脉密度相似，毛细血管密度低。DLL4是动脉规范的驱动因素，因此我们假设Notch1的表达可能参与了动脉粥样硬化的形成。与未携带Tie基因的小鼠相比，未携带Tie基因的小鼠的Notch1基因转录显著上调。我们用可溶性DLL4(SDLL4)刺激小鼠缺血肌肉中的Notch信号。非Tie-sDLL4小鼠毛细血管和小动脉密度显著增加，但血流恢复受阻。结论这些结果表明，尽管血管密度增加，但在血运重建早期激活DLL4可导致无效的血管生成和动脉粥样硬化。这些结果表明，需要完善生长因子的空间和时间平衡，以实现理想的功能和解剖血管重建。
IntroductionArteriolargenesis can be induced by concomitant stimulation of nitric Oxide (NO)‐Angiopoietin receptor (Tie)‐Vascular Endothelial Growth Factor (VEGF) signaling in the rat mesentery angiogenesis assay. We hypothesized that the same combination of exogenously added growth factors would also have a positive impact on arteriolargenesis and, consequently, the recovery of blood flow in a model of unilateral hindlimb ischemia.Results and MethodsNO‐Tie mice had faster blood flow recovery compared to control mice, as assessed by laser speckle imaging. There was no change in capillary density within the ischemic muscles, but arteriole density was higher in NO‐Tie mice. Given the previously documented beneficial effect of VEGF signaling, we tested whether NO‐Tie‐VEGF mice would show further improvement. Surprisingly, these mice recovered no differently from control, arteriole density was similar and capillary density was lower. Dll4 is a driver of arterial specification, so we hypothesized that Notch1 expression would be involved in arteriolargenesis. There was a significant upregulation of Notch1 transcripts in NO‐Tie‐VEGF compared with NO‐Tie mice. Using soluble Dll4 (sDll4), we stimulated Notch signaling in the ischemic muscles of mice. NO‐Tie‐sDll4 mice had significantly increased capillary and arteriole densities, but impaired blood flow recovery.ConclusionThese results suggest that Dll4 activation early on in revascularization can lead to unproductive angiogenesis and arteriolargenesis, despite increased vascular densities. These results suggest spatial and temporal balance of growth factors needs to be perfected for ideal functional and anatomical revascularisation.