血管生成素4(ANGPT4)基因敲除所致小鼠视网膜基因表达的变化分析
首发时间:2024-04-10
摘要:目的:血管生成素(ANGPT1-4)及其内皮受体酪氨酸激酶TIE1和TIE2对血管的发育至关重要。ANGPT4 缺失导致视网膜静脉发育异常,而其分子作用机制尚不清楚。方法:本研究利用Angpt4敲除小鼠模型,分析小鼠新生阶段缺失ANGPT4对血管发育的影响。进一步利用RNA-Seq比较分析了Angpt4基因敲除与对照小鼠视网膜基因表达谱的变化;并利用生信分析工具以确定Angpt4缺失对基因表达的影响以及参与调控的信号途径。结果:敲除Angpt4对小鼠视网膜转录组水平的影响较小,血管新生相关基因的表达未见明显变化。有趣的是,富集分析结果显示上皮间质转化和氧化磷酸化途径显著富集。这些结果提示平滑肌细胞招募异常可能与EMT相关基因的表达下降有关;另外,氧化磷酸化可能影响静脉发育。但除视网膜外,本研究未发现其他组织的静脉与血管发育有明显异常。结论:该研究提示ANGPT4在视网膜静脉形成过程中发挥组织特异性作用,其缺失可能通过影响上皮间质转化和氧化磷酸化途径从而导致静脉成熟重塑异常。
关键词: 血管生成素-4(ANGPT4) 血管发育 视网膜静脉 条件性基因敲除 RNA-Seq
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Changes of gene expression in retina of mice induced by Angpt4 gene knockout
Abstract:Objective: Angiopoietins (ANGPT1-4) and their endothelial receptor tyrosine kinases TIE1 and TIE2 are essential for vascular development. Loss of ANGPT4 leads to abnormal development of retinal veins, but the pathological mechanism is still unclear. Methods: We performed histological analysis of the vascular network in retinas of Angpt4 and control mice by the fluorescent immunostaining to analyze the functional mechanism of ANGPT4 in the formation of retinal veins. RNA-Seq was used to analyze the changes of retinal gene expression after the Angpt4 deletion. Bioinformatics analysis was performed to determine the effect of Angpt4 deletion on the gene expression and signaling pathways.Results: RNA-Seq analysis revealed that only a few genes was significantly changed after ANGPT4 deficiency, and the expression of angiogenesis related genes was not obviously altered. Interestingly, the GSEA analysis showed that the differentially expressed genes were significantly enriched in pathways related to the epithelial-mesenchymal transition (EMT) and the oxidative phosphorylation. These results suggest that the abnormal recruitment of smooth muscle cells may be related to the decreased expression of EMT-related genes. Furthermore, oxidative phosphorylation may cause vascular damages related to the retinal veins . However, there were no obvious vascular abnormalities observed in other tissues. Conclusion: Findings from this study imply that ANGPT4 play an important role in the formation and maturation of retinal veins. While mechanisms underlying the retinal specific functions of ANGPT4 are yet to be defined, the retina transcriptomics analysis suggest that the defective vein formation after Angpt4 deletion may result from the alteration of gene expression related to the epithelial mesenchymal transformation and oxidative phosphorylation pathways.
Keywords: ANGPT4 Vascular development Retinal vein Conditional gene knockout RNA-Seq
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血管生成素4(ANGPT4)基因敲除所致小鼠视网膜基因表达的变化分析
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