EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis.
EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis.
复制标题
DOI：
10.1161/circulationaha.116.026644
复制
发表时间：
2017-08-08
期刊：
影响因子：
37.8
通讯作者：
Orr AW
中科院分区：
文献类型：
--
作者：
Finney AC;Funk SD;Green JM;Yurdagul A Jr;Rana MA;Pistorius R;Henry M;Yurochko A;Pattillo CB;Traylor JG;Chen J;Woolard MD;Kevil CG;Orr AW
动脉粥样硬化斑块的形成是由血管壁的慢性炎症和纤维增殖性重塑引起的。我们之前证明，人类和小鼠动脉粥样硬化斑块中 EphA2 的表达升高，EphA2 是一种参与细胞间相互作用和肿瘤发生的引导分子。在这里，我们通过在动脉粥样硬化小鼠模型 (Apoe-/-) 中删除 EphA2 并通过评估多种血管细胞培养模型中的 EphA2 功能来评估 EphA2 在动脉粥样硬化中的作用。经过 8-16 周的西方饮食后，对雄性和雌性小鼠的大血管动脉粥样硬化负荷进行了评估，并分析了血浆脂质水平。尽管与 Apoe-/- 对照相比，体重增加和血脂水平增加，但 EphA2-/-Apoe-/- 敲除小鼠显示动脉粥样硬化斑块形成减少，其特征是促炎基因表达和斑块巨噬细胞含量减少。虽然斑块巨噬细胞表达 EphA2，但 EphA2 缺失不会影响巨噬细胞表型、炎症反应和脂质摄取，骨髓嵌合体表明造血 EphA2 缺失不会影响斑块形成。相反，内皮 EphA2 敲低显着降低了单核细胞在流动下的牢固粘附。此外，EphA2-/-Apoe-/- 小鼠表现出晚期动脉粥样硬化斑块进展缓慢，平滑肌和胶原蛋白含量减少。与这种表型一致，EphA2 在平滑肌转变为合成表型后表现出增强的表达，并且 EphA2 耗竭会减少动脉粥样硬化斑块和培养的血管平滑肌细胞中的平滑肌增殖、促有丝分裂信号传导和细胞外基质沉积。这些数据共同确定了 EphA2 在动脉粥样硬化中的新作用，调节斑块炎症和晚期动脉粥样硬化病变的进展。细胞培养研究表明，内皮 EphA2 通过促进单核细胞牢固粘附而导致动脉粥样硬化炎症，而平滑肌 EphA2 表达可能通过调节平滑肌增殖和细胞外基质沉积来调节晚期动脉粥样硬化的进展。
Atherosclerotic plaque formation results from chronic inflammation and fibroproliferative remodeling in the vascular wall. We previously demonstrated that both human and mouse atherosclerotic plaques show elevated expression of EphA2, a guidance molecule involved in cell-cell interactions and tumorigenesis. Here, we assessed EphA2's role in atherosclerosis by deleting EphA2 in a mouse model of atherosclerosis (Apoe-/-) and by assessing EphA2 function in multiple vascular cell culture models. Following 8-16 weeks Western diet, male and female mice were assessed for atherosclerotic burden in the large vessels, and plasma lipid levels were analyzed. Despite enhanced weight gain and plasma lipid levels compared to Apoe-/- controls, EphA2-/-Apoe-/- knockout mice show diminished atherosclerotic plaque formation, characterized by reduced proinflammatory gene expression and plaque macrophage content. While plaque macrophages express EphA2, EphA2 deletion does not affect macrophage phenotype, inflammatory responses, and lipid uptake, and bone marrow chimeras suggest hematopoietic EphA2 deletion does not affect plaque formation. In contrast, endothelial EphA2 knockdown significantly reduces monocyte firm adhesion under flow. In addition, EphA2-/-Apoe-/- mice show reduced progression to advanced atherosclerotic plaques with diminished smooth muscle and collagen content. Consistent with this phenotype, EphA2 shows enhanced expression following smooth muscle transition to a synthetic phenotype, and EphA2 depletion reduces smooth muscle proliferation, mitogenic signaling, and extracellular matrix deposition both in atherosclerotic plaques and in vascular smooth muscle cells in culture. Together these data identify a novel role for EphA2 in atherosclerosis, regulating both plaque inflammation and progression to advanced atherosclerotic lesions. Cell culture studies suggest that endothelial EphA2 contributes to atherosclerotic inflammation by promoting monocyte firm adhesion, whereas smooth muscle EphA2 expression may regulate the progression to advanced atherosclerosis by regulating smooth muscle proliferation and extracellular matrix deposition.