Hong Yi-Kai, Cheng Tsung-Lin, Hsu Chao-Kai, Lee Fang-Tzu, Chang Bi-Ing, Wang Kuan-Chieh, Chang Lan-Yun, Wu Hua-Lin, Lai Chao-Han
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Int J Biol Sci. 2024 Jul 2;20(10):3691-3709. doi: 10.7150/ijbs.93526. eCollection 2024.
Tumor endothelial marker 1 (TEM1), an activated mesenchymal cell marker, is implicated in tissue remodeling and repair. Herein, we investigated the role and therapeutic implications of TEM1 in abdominal aortic aneurysm (AAA), a potentially life-threatening aortic disease characterized by vascular inflammation and matrix turnover. Characterization of human AAA revealed increased TEM1 expression derived mainly from medial vascular smooth muscle cells (VSMCs) and adventitial fibroblasts. Bioinformatics analysis demonstrated the association between TEM1-expressing VSMCs and fibroblasts and collagen gene expression. Consistently, collagen content and TEM1 expressed by VSMCs and fibroblasts were increased during CaCl-induced AAA formation in mice. silencing in VSMCs and fibroblasts inhibited transforming growth factor-β1-induced phenotypic change, SMAD2 phosphorylation, and gene expression. Also, deficiency reduced collagen synthesis and exacerbated CaCl-induced AAA formation in mice without disturbing elastin destruction and inflammatory responses. In contrast, rTEM1 promoted phenotypic change and gene expression through SMAD2 phosphorylation in VSMCs and fibroblasts. Treatment with rTEM1 enhanced collagen synthesis, attenuated elastin fragmentation, and inhibited CaCl-induced and angiotensin II-infused AAA formation. In summary, TEM1 in resident stromal cells regulates collagen synthesis to counteract aortic wall failure during AAA formation. Matrix integrity restored by rTEM1 treatment may hold therapeutic potential against AAA.
肿瘤内皮标志物1（TEM1）是一种活化的间充质细胞标志物，与组织重塑和修复有关。在此，我们研究了TEM1在腹主动脉瘤（AAA）中的作用及治疗意义，AAA是一种潜在的危及生命的主动脉疾病，其特征为血管炎症和基质更新。对人AAA的特征分析显示，TEM1表达增加，主要来源于血管中膜的血管平滑肌细胞（VSMCs）和外膜成纤维细胞。生物信息学分析表明，表达TEM1的VSMCs和成纤维细胞与胶原蛋白基因表达之间存在关联。同样，在氯化钙诱导的小鼠AAA形成过程中，VSMCs和成纤维细胞表达的胶原蛋白含量和TEM1均增加。VSMCs和成纤维细胞中的基因沉默抑制了转化生长因子-β1诱导的表型变化、SMAD2磷酸化和基因表达。此外，基因缺陷减少了胶原蛋白合成，并加剧了氯化钙诱导的小鼠AAA形成，而未干扰弹性蛋白破坏和炎症反应。相反，重组TEM1（rTEM1）通过VSMCs和成纤维细胞中的SMAD2磷酸化促进表型变化和基因表达。用rTEM1治疗可增强胶原蛋白合成，减轻弹性蛋白断裂，并抑制氯化钙诱导的和血管紧张素II灌注诱导的AAA形成。总之，驻留基质细胞中的TEM1调节胶原蛋白合成，以对抗AAA形成过程中的主动脉壁衰竭。rTEM1治疗恢复的基质完整性可能对AAA具有治疗潜力。
