Finney Alexandra C, Funk Steven D, Green Jonette M, Yurdagul Arif, Rana Mohammad Atif, Pistorius Rebecca, Henry Miriam, Yurochko Andrew, Pattillo Christopher B, Traylor James G, Chen Jin, Woolard Matthew D, Kevil Christopher G, Orr A Wayne
From Departments of Cell Biology and Anatomy (A.C.F., S.D.F., J.M.G., A. Yurdagul, C.G.K., A.W.O.), Pathology and Translational Pathobiology (J.M.G., A. Yurdagul, R.P., M.H., J.G.T., C.G.K., A.W.O.), Cardiology (M.A.R.), Microbiology and Immunology (A. Yurochko, M.D.W.), and Molecular and Cellular Physiology (C.B.P., C.G.K., A.W.O.), Louisiana State University Health Sciences Center-Shreveport; Departments of Cancer Biology and Cell and Developmental Biology, Vanderbilt University, Nashville, TN (J.C.); and Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville (J.C.).
Circulation. 2017 Aug 8;136(6):566-582. doi: 10.1161/CIRCULATIONAHA.116.026644. Epub 2017 May 9.
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 the role of EphA2 in atherosclerosis by deleting EphA2 in a mouse model of atherosclerosis (Apoe) and by assessing EphA2 function in multiple vascular cell culture models. After 8 to 16 weeks on a 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 with Apoe controls, EphA2Apoe knockout mice show diminished atherosclerotic plaque formation, characterized by reduced proinflammatory gene expression and plaque macrophage content. Although plaque macrophages express EphA2, EphA2 deletion does not affect macrophage phenotype, inflammatory responses, and lipid uptake, and bone marrow chimeras suggest that hematopoietic EphA2 deletion does not affect plaque formation. In contrast, endothelial EphA2 knockdown significantly reduces monocyte firm adhesion under flow. In addition, EphA2Apoe mice show reduced progression to advanced atherosclerotic plaques with diminished smooth muscle and collagen content. Consistent with this phenotype, EphA2 shows enhanced expression after 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.
动脉粥样硬化斑块形成是血管壁慢性炎症和纤维增生性重塑的结果。我们之前证明，人类和小鼠动脉粥样硬化斑块中EphA2的表达均升高，EphA2是一种参与细胞间相互作用和肿瘤发生的导向分子。
在此，我们通过在动脉粥样硬化小鼠模型（Apoe）中删除EphA2，并在多个血管细胞培养模型中评估EphA2的功能，来评估EphA2在动脉粥样硬化中的作用。在西方饮食喂养8至16周后，对雄性和雌性小鼠的大血管动脉粥样硬化负担进行评估，并分析血浆脂质水平。
尽管与Apoe对照组相比，EphA2Apoe基因敲除小鼠体重增加且血浆脂质水平升高，但其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降低。尽管斑块巨噬细胞表达EphA2，但EphA2缺失并不影响巨噬细胞表型、炎症反应和脂质摄取，骨髓嵌合体表明造血EphA2缺失不影响斑块形成。相反，内皮细胞EphA2基因敲低显著降低流动状态下单核细胞的牢固黏附。此外，EphA2Apoe小鼠进展为晚期动脉粥样硬化斑块的情况减少，平滑肌和胶原蛋白含量降低。与这种表型一致，EphA2在平滑肌转变为合成表型后表达增强，EphA2缺失减少了动脉粥样硬化斑块和平滑肌细胞培养物中平滑肌的增殖、有丝分裂信号传导和细胞外基质沉积。
总之，这些数据确定了EphA2在动脉粥样硬化中的新作用，即调节斑块炎症和向晚期动脉粥样硬化病变的进展。细胞培养研究表明，内皮细胞EphA2通过促进单核细胞牢固黏附促进动脉粥样硬化炎症，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向晚期动脉粥样硬化的进展。
