Activating Notch signaling post-SCI modulates angiogenesis in penumbral vascular beds but does not improve hindlimb locomotor recovery.
Activating Notch signaling post-SCI modulates angiogenesis in penumbral vascular beds but does not improve hindlimb locomotor recovery.
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DOI：
10.1016/j.expneurol.2010.12.002
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发表时间：
2011-02
影响因子：
5.3
通讯作者：
Whittemore, Scott R.
中科院分区：
文献类型：
--
作者：
Fassbender, Janelle M.;Myers, Scott A.;Whittemore, Scott R.
Notch信号的操纵已经导致显著的肿瘤缩小以及从几种创伤和缺血性损伤模型中恢复，表明其潜在的临床应用。我们已经测试了Notch信号的激动剂和拮抗剂，以研究Notch介导的血管生成对创伤性损伤后脊髓血管病理学的影响。最初的新生儿视网膜血管化试验显示了它们各自的体内生物活性。在胸部中部挫伤后立即通过初始颈静脉推注和尾静脉注射用拮抗剂锯齿状蛋白1-Fc嵌合体（Jag 1-Fc）或激动剂刻缺蛋白1抗体（N1 Ab）治疗小鼠，持续损伤后3天。14天后，与对照组相比，激活Notch信号传导降低了半影灰质内的总体血管密度，同时保持了灌注血管的密度。抑制Notch信号传导并不改变病变半影区内微血管的密度或灌注。此外，Notch信号的激活或抑制均未显著改变震中和半影区的炎症、缺氧和病变体积。重要的是，两种治疗都没有改变运动功能。在出生后视网膜血管测定中，Jag 1-Fc和N1 Ab的给药分别增加和减少了每种治疗中的尖端细胞数量和分支点。然而，尽管Notch配体表达充足，但这些药物在体外不调节原发性CNS EC增殖。我们的结论是，Notch信号，而发育血管生成的重要组成部分，可能发挥较小的作用，在介导血管恢复创伤性损伤后的中枢神经系统。
Manipulation of Notch signaling has led to significant tumor shrinkage as well as recovery from several traumatic and ischemic injury models indicating its potential clinical application. We have tested both an agonist and antagonist of Notch signaling to study the effects of Notch-mediated angiogenesis on spinal cord vascular pathology following traumatic injury. Initial neonatal retinal vascularization assays showed their respective bioactivities in vivo. Mice were treated with either the antagonist Jagged1-Fc chimera (Jag1-Fc) or agonist Notch1 antibody (N1 Ab) immediately following a mid-thoracic contusive injury through an initial jugular bolus and tail vein injections for 3 days post-injury. After 14 days, activating Notch signaling decreased the overall vascular density within the penumbral gray matter compared to controls while maintaining the density of perfused vessels. Inhibiting Notch signaling did not change the density or perfusion of microvessels within the lesion penumbra. Furthermore, neither activation nor inhibition of Notch signaling significantly altered inflammation, hypoxia, and lesion volume in the epicenter and penumbra. Importantly, neither treatment changed locomotor function. In postnatal retinal vascular assays, administration of Jag1-Fc and N1 Ab increased and decreased both tip cell numbers and branch points in each treatment, respectively. However, these agents did not modulate primary CNS EC proliferation in vitro in spite of sufficient Notch ligand expression. We conclude that Notch signaling, while an important part of developmental angiogenesis, may play a lesser role in mediating vascular recovery following traumatic injury to the CNS.
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