Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, 400715 Chongqing, China.
University of Chinese Academy of Sciences (Chongqing), Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Beibei, 400714 Chongqing, China.
Development. 2022 Jul 1;149(13). doi: 10.1242/dev.200729. Epub 2022 Jun 30.
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 Cxcl12b/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 pro-angiogenic therapies.
在缺血性中风后，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治疗的主要挑战。新生血管（BVs）如何被正确引导到缺血性梗死区域的分子机制尚不清楚。在这里，我们使用斑马鱼脑血管损伤模型，表明趋化因子信号提供了关键的导向线索，决定了内生长的淋巴管（iLVs）的生长方向，并进而决定了新生 BVs 的生长方向。趋化因子受体 Cxcr4a 在损伤后 iLVs 中转录激活，而其配体 Cxcl12b 在残留的中央 BVs 中表达，iLV 内生长的目的地。突变体和嵌合体研究表明，Cxcl12b/Cxcr4a 介导的趋化作用对于确定 iLVs 和新生 BVs 的生长方向是必要且充分的。这项研究为脑血管再生的血管方向性如何被正确确定提供了分子基础，提示 Cxcl12b/Cxcr4a 在缺血后促血管生成治疗的发展中有潜在的应用。
