Brain vascular damage-induced lymphatic ingrowth is directed by Cxcl12b/Cxcr4a
Brain vascular damage-induced lymphatic ingrowth is directed by Cxcl12b/Cxcr4a
复制标题
脑血管损伤诱导的淋巴管向内生长由 Cxcl12b/Cxcr4a 指导
DOI：
10.1242/dev.200729
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发表时间：
2022-07-01
期刊：
影响因子：
4.6
通讯作者：
Luo, Lingfei
中科院分区：
文献类型：
--
作者：
Chen, Jingying;He, Jianbo;Luo, Lingfei
缺血性卒中后，促进血管再生而不引起不受控制的血管生长似乎是促血管生成疗法的主要挑战。新生血管（BV）如何被正确引导到缺血后梗死区域的分子机制仍然未知。在这里，使用斑马鱼脑血管损伤模型，我们表明趋化因子信号提供了关键的指导线索，以确定向内生长的淋巴管（iLV）的生长方向，反过来，新生的BV。趋化因子受体Cxcr 4a在损伤后的iLV中被转录激活，而其配体Cxcl 12 b在残留的中央BV中表达，这是iLV向内生长的目的地。突变体和嵌合体研究表明，Cxc 112 b/Cxcr 4a介导的趋化性是必要的，足以确定生长方向的iLV和新生的BV。本研究为如何正确确定脑血管再生的血管方向性提供了分子基础，表明Cxcl 12 b/Cxcr 4a在缺血后促血管生成疗法的发展中的潜在应用。
After ischemic stroke, promotion of vascular regeneration without causing uncontrolled vessel growth appears to be the major challenge for pro-angiogenic therapies. The molecular mechanisms underlying how nascent blood vessels (BVs) are correctly guided into the post-ischemic infarction area remain unknown. Here, using a zebrafish cerebrovascular injury model, we show that chemokine signaling provides crucial guidance cues to determine the growing direction of ingrown lymphatic vessels (iLVs) and, in turn, that of nascent BVs. The chemokine receptor Cxcr4a is transcriptionally activated in the iLVs after injury, whereas its ligand Cxcl12b is expressed in the residual central BVs, the destinations of iLV ingrowth. Mutant and mosaic studies indicate that Cxc112b/Cxcr4a-mediated chemotaxis is necessary and sufficient to determine the growing direction of iLVs and nascent BVs. This study provides a molecular basis for how the vessel directionality of cerebrovascular regeneration is properly determined, suggesting potential application of Cxcl12b/Cxcr4a in the development of post-ischemic proangiogenic therapies.