Loss of Smooth Muscle Tenascin-X Inhibits Vascular Remodeling Through Increased TGF-β Signaling.

IF 7.4 1区 医学 Q1 HEMATOLOGY Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2024-08-01 Epub Date: 2024-06-27 DOI:10.1161/ATVBAHA.123.321067
Guozheng Liang, Xiao-Fei Lv, Wei Huang, Young-June Jin, Kenneth Anthony Roquid, Haruya Kawase, Stefan Offermanns
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Abstract

Background: Vascular smooth muscle cells (VSMCs) are highly plastic. Vessel injury induces a phenotypic transformation from differentiated to dedifferentiated VSMCs, which involves reduced expression of contractile proteins and increased production of extracellular matrix and inflammatory cytokines. This transition plays an important role in several cardiovascular diseases such as atherosclerosis, hypertension, and aortic aneurysm. TGF-β (transforming growth factor-β) is critical for VSMC differentiation and to counterbalance the effect of dedifferentiating factors. However, the mechanisms controlling TGF-β activity and VSMC phenotypic regulation under in vivo conditions are poorly understood. The extracellular matrix protein TN-X (tenascin-X) has recently been shown to bind TGF-β and to prevent it from activating its receptor.

Methods: We studied the role of TN-X in VSMCs in various murine disease models using tamoxifen-inducible SMC-specific knockout and adeno-associated virus-mediated knockdown.

Results: In hypertensive and high-fat diet-fed mice, after carotid artery ligation as well as in human aneurysmal aortae, expression of Tnxb, the gene encoding TN-X, was increased in VSMCs. Mice with smooth muscle cell-specific loss of TN-X (SMC-Tnxb-KO) showed increased TGF-β signaling in VSMCs, as well as upregulated expression of VSMC differentiation marker genes during vascular remodeling compared with controls. SMC-specific TN-X deficiency decreased neointima formation after carotid artery ligation and reduced vessel wall thickening during Ang II (angiotensin II)-induced hypertension. SMC-Tnxb-KO mice lacking ApoE showed reduced atherosclerosis and Ang II-induced aneurysm formation under high-fat diet. Adeno-associated virus-mediated SMC-specific expression of short hairpin RNA against Tnxb showed similar beneficial effects. Treatment with an anti-TGF-β antibody or additional SMC-specific loss of the TGF-β receptor reverted the effects of SMC-specific TN-X deficiency.

Conclusions: In summary, TN-X critically regulates VSMC plasticity during vascular injury by inhibiting TGF-β signaling. Our data indicate that inhibition of vascular smooth muscle TN-X may represent a strategy to prevent and treat pathological vascular remodeling.

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平滑肌 Tenascin-X 的缺失通过增加 TGF-β 信号抑制血管重塑
背景:血管平滑肌细胞(VSMC血管平滑肌细胞(VSMC)具有高度可塑性。血管损伤会诱导血管平滑肌细胞从分化型向去分化型的表型转变,其中包括收缩蛋白的表达减少,细胞外基质和炎症细胞因子的产生增加。这种转变在动脉粥样硬化、高血压和主动脉瘤等多种心血管疾病中起着重要作用。TGF-β(转化生长因子-β)对 VSMC 的分化和抵消去分化因子的作用至关重要。然而,人们对体内条件下控制 TGF-β 活性和 VSMC 表型调节的机制知之甚少。最近的研究表明,细胞外基质蛋白 TN-X(tenascin-X)可与 TGF-β 结合,并阻止其激活受体:方法:我们利用他莫昔芬诱导的SMC特异性基因敲除和腺相关病毒介导的基因敲除,研究了TN-X在各种小鼠疾病模型中VSMC中的作用:结果:在高血压和高脂饮食喂养的小鼠、颈动脉结扎后以及人类动脉瘤主动脉中,编码 TN-X 的基因 Tnxb 在 VSMCs 中的表达增加。与对照组相比,平滑肌细胞特异性 TN-X 缺失的小鼠(SMC-Tnxb-KO)在血管重塑过程中表现出血管内皮生长因子-β信号转导增加,血管内皮生长因子-β分化标记基因表达上调。SMC特异性TN-X缺乏症可减少颈动脉结扎后新生内膜的形成,并减少血管紧张素II诱导的高血压过程中血管壁的增厚。缺乏载脂蛋白E的SMC-Tnxb-KO小鼠在高脂饮食条件下动脉粥样硬化和Ang II诱导的动脉瘤形成减少。腺相关病毒介导的 SMC 特异性表达抗 Tnxb 的短发夹 RNA 也显示出类似的有益效果。用抗 TGF-β 抗体或额外的 SMC 特异性 TGF-β 受体缺失治疗可恢复 SMC 特异性 TN-X 缺失的效果:总之,TN-X 通过抑制 TGF-β 信号传导,在血管损伤过程中对 VSMC 的可塑性起着至关重要的调节作用。我们的数据表明,抑制血管平滑肌 TN-X 可能是预防和治疗病理性血管重塑的一种策略。
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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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