Differential Roles of Endothelial Cell-Derived and Smooth Muscle Cell-Derived Fibronectin Containing Extra Domain A in Early and Late Atherosclerosis
Differential Roles of Endothelial Cell-Derived and Smooth Muscle Cell-Derived Fibronectin Containing Extra Domain A in Early and Late Atherosclerosis
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DOI：
10.1161/atvbaha.120.314459
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发表时间：
2020-07-01
影响因子：
8.7
通讯作者：
Chauhan, Anil K.
中科院分区：
文献类型：
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作者：
Doddapattar, Prakash;Dev, Rishabh;Chauhan, Anil K.
目的：动脉粥样硬化动脉的细胞外基质含有丰富的细胞Fn-EDA（纤连蛋白含有额外的结构域A）的存款，这表明在动脉粥样硬化的病理生理功能的作用。Fn-EDA由几种细胞类型合成，包括内皮细胞（EC）和平滑肌细胞（SMC），已知它们有助于动脉粥样硬化的不同阶段。尽管先前使用整体Fn-EDA缺陷小鼠的研究已经证明Fn-EDA是促动脉粥样硬化的，但EC与SMC衍生的Fn-EDA在动脉粥样硬化中的细胞特异性作用尚未被研究。方法和结果：为了确定不同Fn-EDA库在动脉粥样硬化中的相对贡献，我们在载脂蛋白E缺陷（Apoe（-/-））背景下产生EC（Fn-EDA（EC-KO））或平滑肌细胞（Fn-EDA（SMC-KO））中缺乏Fn-EDA的突变株。在喂食高脂肪西方饮食4周（早期动脉粥样硬化）或14周（晚期动脉粥样硬化）的雄性和雌性小鼠中，在整个动脉和主动脉窦的横截面中评价动脉粥样硬化病变进展的程度。无论性别如何，Fn-EDA（EC-KO）小鼠（而非Fn-EDA（SMC-KO）小鼠）均表现出早期动脉粥样硬化形成显著减少，同时斑块内炎性细胞（中性粒细胞和巨噬细胞）和VCAM-1（血管细胞粘附分子-1）表达水平降低。在晚期动脉粥样硬化模型中，无论性别如何，Fn-EDA（SMC-KO）小鼠表现出显著降低的动脉粥样硬化形成，但Fn-EDA（EC-KO）小鼠则没有，这伴随着斑块内巨噬细胞含量的降低。各组间病变SMC、胶原含量和血浆炎性细胞因子（TNF-α [肿瘤坏死因子-α]和IL-1 β [白细胞介素-1 β]）、总胆固醇和甘油三酯水平相当。结论：EC来源的Fn-EDA参与早期动脉粥样硬化，而SMC来源的Fn-EDA参与晚期动脉粥样硬化。
Objective: The extracellular matrix of atherosclerotic arteries contains abundant deposits of cellular Fn-EDA (fibronectin containing extra domain A), suggesting a functional role in the pathophysiology of atherosclerosis. Fn-EDA is synthesized by several cell types, including endothelial cells (ECs) and smooth muscle cells (SMCs), which are known to contribute to different stages of atherosclerosis. Although previous studies using global Fn-EDA-deficient mice have demonstrated that Fn-EDA is proatherogenic, the cell-specific role of EC versus SMC-derived-Fn-EDA in atherosclerosis has not been investigated yet. Approach and Results: To determine the relative contribution of different pools of Fn-EDA in atherosclerosis, we generated mutant strains lacking Fn-EDA in the ECs (Fn-EDA(EC-KO)) or smooth muscle cells (Fn-EDA(SMC-KO)) on apolipoprotein E-deficient (Apoe(-/-)) background. The extent of atherosclerotic lesion progression was evaluated in whole aortae, and cross-sections of the aortic sinus in male and female mice fed a high-fat Western diet for either 4 weeks (early atherosclerosis) or 14 weeks (late atherosclerosis). Irrespective of sex, Fn-EDA(EC-KO), but not Fn-EDA(SMC-KO)mice, exhibited significantly reduced early atherogenesis concomitant with decrease in inflammatory cells (neutrophil and macrophage) and VCAM-1 (vascular cell adhesion molecule-1) expression levels within the plaques. In late atherosclerosis model, irrespective of sex, Fn-EDA(SMC-KO)mice exhibited significantly reduced atherogenesis, but not Fn-EDA(EC-KO)mice, that was concomitant with decreased macrophage content within plaques. Lesional SMCs, collagen content, and plasma inflammatory cytokines (TNF-alpha [tumor necrosis factor-alpha] and IL-1 beta [interleukin-1 beta]), total cholesterol, and triglyceride levels were comparable among groups. Conclusions: EC-derived Fn-EDA contributes to early atherosclerosis, whereas SMC-derived Fn-EDA contributes to late atherosclerosis.