Endothelial FN (Fibronectin) Deposition by α5β1 Integrins Drives Atherogenic Inflammation.
Endothelial FN (Fibronectin) Deposition by α5β1 Integrins Drives Atherogenic Inflammation.
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DOI：
10.1161/atvbaha.118.311705
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发表时间：
2018-11
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影响因子：
--
通讯作者：
Orr AW
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作者：
Al-Yafeai Z;Yurdagul A Jr;Peretik JM;Alfaidi M;Murphy PA;Orr AW
细胞外基质数量和组成的改变有助于动脉粥样硬化，在病变发展之前，内皮下基底膜重塑为富含纤维连接蛋白的基质。内皮细胞与纤连蛋白的相互作用引发了对多种致动脉粥样硬化刺激的炎症反应;然而，调节早期致动脉粥样硬化纤连蛋白积聚的机制仍然未知。我们先前证明氧化低密度脂蛋白（oxLDL）通过激活整合素α5β1（纤连蛋白原纤维形成的经典介质）促进内皮促炎基因表达。我们现在发现oxLDL驱动了强大的内皮纤连蛋白沉积，抑制α5β1（阻断抗体，α5敲除细胞）完全抑制了oxLDL诱导的纤连蛋白沉积。与此一致，ApoE基因敲除小鼠中可诱导的内皮特异性α5整合素缺失显著减少动脉粥样硬化斑块形成，与早期致动脉粥样硬化性炎症减少相关。与TGFβ诱导的纤连蛋白沉积不同，oxLDL不诱导纤连蛋白表达（mRNA，蛋白质）或内皮-间充质转化表型。此外，我们表明，细胞衍生的和血浆衍生的纤连蛋白差异影响内皮功能，只有细胞衍生的纤连蛋白能够支持oxLDL诱导的VCAM-1的表达，尽管血浆纤连蛋白沉积oxLDL。在细胞衍生的纤连蛋白中包含EIIIA和EIIIB结构域介导了这种作用，因为EIIIA/EIIIB敲除的内皮细胞显示出减少的oxLDL诱导的炎症。此外，我们的数据表明，EIIIA/EIIIB阳性细胞纤连蛋白是最大化α5β1募集到粘着斑和纤连蛋白原纤维形成所必需的。总之，我们的数据表明，内皮α5整合素驱动oxLDL诱导的纤连蛋白沉积和早期致动脉粥样硬化炎症。此外，我们发现α5β1依赖性内皮纤连蛋白沉积介导oxLDL依赖性内皮炎症和纤连蛋白原纤维形成。
Alterations in extracellular matrix quantity and composition contribute to atherosclerosis, with remodeling of the subendothelial basement membrane to a fibronectin-rich matrix preceding lesion development. Endothelial cell interactions with fibronectin prime inflammatory responses to a variety of atherogenic stimuli; however, the mechanisms regulating early atherogenic fibronectin accumulation remain unknown. We previously demonstrated that oxidized LDL (oxLDL) promotes endothelial pro inflammatory gene expression by activating the integrin α5β1, a classic mediator of fibronectin fibrillogenesis. We now show that oxLDL drives robust endothelial fibronectin deposition and inhibiting α5β1 (blocking antibodies, α5 knockout cells) completely inhibits oxLDL-induced fibronectin deposition. Consistent with this, inducible endothelial-specific α5 integrin deletion in ApoE knockout mice significantly reduces atherosclerotic plaque formation, associated with reduced early atherogenic inflammation. Unlike TGFβ-induced fibronectin deposition, oxLDL does not induce fibronectin expression (mRNA, protein) or the endothelial-to-mesenchymal transition phenotype. In addition, we show that cell-derived and plasma-derived fibronectin differentially affect endothelial function, with only cell-derived fibronectin capable of supporting oxLDL-induced VCAM-1 expression despite plasma fibronectin deposition by oxLDL. The inclusion of EIIIA and EIIIB domains in cell-derived fibronectin mediates this effect, as EIIIA/EIIIB knockout endothelial cells show diminished oxLDL-induced inflammation. Furthermore, our data suggests that EIIIA/EIIIB-positive cellular fibronectin is required for maximal α5β1 recruitment to focal adhesions and fibronectin fibrillogenesis. Taken together, our data demonstrate that endothelial α5 integrins drives oxLDL-induced fibronectin deposition and early atherogenic inflammation. Additionally, we show that α5β1-dependent endothelial fibronectin deposition mediates oxLDL-dependent endothelial inflammation and fibronectin fibrillogenesis.