Transforming growth factor-beta 1 produced by vascular smooth muscle cells predicts fibrosis in the gastrocnemius of patients with peripheral artery disease.
Transforming growth factor-beta 1 produced by vascular smooth muscle cells predicts fibrosis in the gastrocnemius of patients with peripheral artery disease.
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DOI：
10.1186/s12967-016-0790-3
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发表时间：
2016-02-04
影响因子：
7.4
通讯作者：
Casale GP
中科院分区：
文献类型：
--
作者：
Ha DM;Carpenter LC;Koutakis P;Swanson SA;Zhu Z;Hanna M;DeSpiegelaere HK;Pipinos II;Casale GP
下肢缺血、肌病和肢体功能障碍是外周动脉疾病（PAD）的显著特征。PAD肌病的特征在于与细胞外基质扩张相关的肌纤维变性和转化生长因子-β 1（TGF-β1;一种促纤维化细胞因子）表达增加。在这项研究中，我们评估了TGF-β1在对照组（CTRL）和PAD患者腓肠肌中的细胞表达及其与胶原沉积、成纤维细胞积聚和肢体血流动力学的关系。腓肠肌活检收集自伴跛行（PAD-II; N = 25）和组织缺损（PAD-IV; N = 20）的PAD患者和CTRL患者（N = 20）。用荧光抗体标记载玻片标本中的TGF-β1，并通过定量宽视野荧光显微镜进行分析。我们评估了TGF-β1与血管平滑肌细胞（SMC）（高分子量钙调蛋白）、成纤维细胞（TE-7抗原）、巨噬细胞（CD 163）、T细胞（CD 3）和内皮细胞（CD 31）的共定位。胶原蛋白用Masson三色染色，胶原蛋白密度通过具有多光谱成像的定量明场显微镜测定。胶原密度从CTRL到PAD-II再到PAD-IV标本增加（所有差异p < 0.05），并且在微血管周围突出。TGF-β1表达随疾病进展而增加（所有差异p < 0.05），与所有标本中的胶原密度相关（r = 0.864; p < 0.001），与成纤维细胞积聚相关，仅在SMC中观察到。在PAD患者中，TGF-β1表达与踝臂指数呈负相关（r =-0.698; p < 0.001）。我们的研究结果支持PAD患者腓肠肌进行性纤维化，这是由组织缺氧引起的微血管SMC中TGF-β1的产生增加引起的。本文的在线版本（doi：10.1186/s12967-016-0790-3）包含补充材料，可供授权用户使用。
Lower leg ischemia, myopathy, and limb dysfunction are distinguishing features of peripheral artery disease (PAD). The myopathy of PAD is characterized by myofiber degeneration in association with extracellular matrix expansion, and increased expression of transforming growth factor-beta 1 (TGF-β1; a pro-fibrotic cytokine). In this study, we evaluated cellular expression of TGF-β1 in gastrocnemius of control (CTRL) and PAD patients and its relationship to deposited collagen, fibroblast accumulation and limb hemodynamics. Gastrocnemius biopsies were collected from PAD patients with claudication (PAD-II; N = 25) and tissue loss (PAD-IV; N = 20) and from CTRL patients (N = 20). TGF-β1 in slide-mounted specimens was labeled with fluorescent antibodies and analyzed by quantitative wide-field, fluorescence microscopy. We evaluated co-localization of TGF-β1 with vascular smooth muscle cells (SMC) (high molecular weight caldesmon), fibroblasts (TE-7 antigen), macrophages (CD163), T cells (CD3) and endothelial cells (CD31). Collagen was stained with Masson Trichrome and collagen density was determined by quantitative bright-field microscopy with multi-spectral imaging. Collagen density increased from CTRL to PAD-II to PAD-IV specimens (all differences p < 0.05) and was prominent around microvessels. TGF-β1 expression increased with advancing disease (all differences p < 0.05), correlated with collagen density across all specimens (r = 0.864; p < 0.001), associated with fibroblast accumulation, and was observed exclusively in SMC. TGF-β1 expression inversely correlated with ankle-brachial index across PAD patients (r = −0.698; p < 0.001). Our findings support a progressive fibrosis in the gastrocnemius of PAD patients that is caused by elevated TGF-β1 production in the SMC of microvessels in response to tissue hypoxia. The online version of this article (doi:10.1186/s12967-016-0790-3) contains supplementary material, which is available to authorized users.