Low-dosage inhibition of Dll4 signaling promotes wound healing by inducing functional neo-angiogenesis.
Low-dosage inhibition of Dll4 signaling promotes wound healing by inducing functional neo-angiogenesis.
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DOI：
10.1371/journal.pone.0029863
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Duarte A
中科院分区：
文献类型：
--
作者：
Trindade A;Djokovic D;Gigante J;Badenes M;Pedrosa AR;Fernandes AC;Lopes-da-Costa L;Krasnoperov V;Liu R;Gill PS;Duarte A
最近关于Dll4在生理和病理条件下功能的研究表明，这种Notch配体可能是一个重要的治疗靶点。Dll4似乎是一种主要的抗血管生成剂，在各种血管生成途径中发挥核心作用。抗dll4治疗在小鼠中的第一次试验显示了一种矛盾的效果，因为它减少了肿瘤灌注和生长，尽管导致血管密度增加。这被认为是由于新形成的血管不够成熟，导致循环缺陷和肿瘤缺氧增加。由于已知Dll4的功能密切依赖于表达水平，我们设想可以调节治疗性抗Dll4剂量，从而增加功能充分的血管。这在血管功能是限制恢复因素的情况下是有用的，比如伤口愈合和组织缺氧，尤其是糖尿病患者。我们在小鼠身上的实验结果证实了这种可能性，揭示了低剂量抑制Dll4/Notch信号可以改善血管功能并加速伤口愈合。
Recent findings regarding Dll4 function in physiological and pathological conditions indicate that this Notch ligand may constitute an important therapeutic target. Dll4 appears to be a major anti-angiogenic agent, occupying a central role in various angiogenic pathways. The first trials of anti-Dll4 therapy in mice demonstrated a paradoxical effect, as it reduced tumor perfusion and growth despite leading to an increase in vascular density. This is seen as the result of insufficient maturation of the newly formed vasculature causing a circulatory defect and increased tumor hypoxia. As Dll4 function is known to be closely dependent on expression levels, we envisioned that the therapeutic anti-Dll4 dosage could be modulated to result in the increase of adequately functional blood vessels. This would be useful in conditions where vascular function is a limiting factor for recovery, like wound healing and tissue hypoxia, especially in diabetic patients. Our experimental results in mice confirmed this possibility, revealing that low dosage inhibition of Dll4/Notch signaling causes improved vascular function and accelerated wound healing.