CXCL12-CXCR4 信号在主动脉弓和肺动脉的正常形态发生中起着至关重要的作用。
CXCL12-CXCR4 signalling plays an essential role in proper patterning of aortic arch and pulmonary arteries.
机构信息
Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Gaetbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea.
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 1600 SW Archer Road, Room CG-20B, Gainesville, FL 32610, USA.
出版信息
Cardiovasc Res. 2017 Nov 1;113(13):1677-1687. doi: 10.1093/cvr/cvx188.
AIMS
Chemokine CXCL12 (stromal derived factor 1: SDF1) has been shown to play important roles in various processes of cardiovascular development. In recent avian studies, CXCL12 signalling has been implicated in guidance of cardiac neural crest cells for their participation in the development of outflow tract and cardiac septum. The goal of this study is to investigate the extent to which CXCL12 signalling contribute to the development of aortic arch and pulmonary arteries in mammals.
METHODS AND RESULTS
Novel Cxcl12-LacZ reporter and conditional alleles were generated. Using whole mount X-gal staining with the reporter allele and vascular casting techniques, we show that the domain branching pattern of pulmonary arteries in Cxcl12-null mice is completely disrupted and discordant with that of pulmonary veins and airways. Cxcl12-null mice also displayed abnormal and superfluous arterial branches from the aortic arch. The early steps of pharyngeal arch remodelling in Cxcl12-null mice appeared to be unaffected, but vertebral arteries were often missing and prominent aberrant arteries were present parallel to carotid arteries or trachea, similar to aberrant vertebral artery or thyroid ima artery, respectively. Analysis with computed tomography not only confirmed the results from vascular casting studies but also identified abnormal systemic arterial supply to lungs in the Cxcl12-null mice. Tie2-Cre mediated Cxcr4 deletion phenocopied the Cxcl12-null phenotypes, indicating that CXCR4 is the primary receptor for arterial patterning, whereas Cxcl12 or Cxcr4 deletion by Wnt1-Cre did not affect aortic arch patterning.
CONCLUSION
CXCL12-CXCR4 signalling is essential for the correct patterning of aortic arches and pulmonary arteries during development. Superfluous arteries in Cxcl12-null lungs and the aortic arch infer a role of CXCL12 in protecting arteries from uncontrolled sprouting during development of the arterial system.
目的
趋化因子 CXCL12（基质衍生因子 1：SDF1）已被证明在心血管发育的各个过程中发挥重要作用。在最近的禽类研究中，CXCL12 信号已被牵连到心脏神经嵴细胞的导向，以参与流出道和心脏中隔的发育。本研究的目的是研究 CXCL12 信号在哺乳动物主动脉弓和肺动脉发育中的作用程度。
方法和结果
生成了新型 Cxcl12-LacZ 报告基因和条件等位基因。使用报告基因等位基因的全胚胎 X-gal 染色和血管铸型技术，我们表明，Cxcl12 缺失小鼠的肺动脉分支模式完全被破坏，与肺静脉和气道不一致。Cxcl12 缺失小鼠也显示出主动脉弓的异常和多余的动脉分支。Cxcl12 缺失小鼠的咽弓重塑的早期步骤似乎没有受到影响，但椎动脉经常缺失，并且与颈动脉或气管平行存在明显的异常动脉，分别类似于异常椎动脉或甲状腺 ima 动脉。计算机断层扫描分析不仅证实了血管铸型研究的结果，还确定了 Cxcl12 缺失小鼠肺部异常的全身动脉供应。Tie2-Cre 介导的 Cxcr4 缺失表现出与 Cxcl12 缺失表型相似，表明 CXCR4 是动脉模式形成的主要受体，而 Wnt1-Cre 介导的 Cxcl12 或 Cxcr4 缺失不影响主动脉弓模式形成。
结论
CXCL12-CXCR4 信号在发育过程中对主动脉弓和肺动脉的正确模式形成至关重要。Cxcl12 缺失小鼠肺部和主动脉弓中的多余动脉表明 CXCL12 在保护动脉免受发育中动脉系统不受控制的发芽方面发挥作用。
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