Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
Nat Metab. 2019 Sep;1(9):912-926. doi: 10.1038/s42255-019-0102-3. Epub 2019 Aug 26.
Atherosclerosis is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined. Here we show that endothelial TGFβ signaling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Inhibition of endothelial TGFβ signaling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These pro-inflammatory effects of endothelial TGFβ signaling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type specific therapeutic intervention aimed at control of this disease.
动脉粥样硬化是一种由异常剪切力和内皮脂质蓄积相互作用引发的进行性血管疾病。这些因素以及潜在的其他因素共同导致血管壁发生慢性炎症反应，据认为这是导致疾病进展的原因，其特征是动脉粥样硬化斑块的积累。然而，负责维持斑块炎症和斑块生长的分子事件尚未完全确定。在这里，我们表明内皮 TGFβ 信号是与动脉粥样硬化相关的血管炎症的主要驱动因素之一。在高脂血症小鼠中抑制内皮 TGFβ 信号可减少血管壁炎症和血管通透性，并导致疾病进展停止和已建立的病变消退。内皮 TGFβ 信号的这些促炎作用与它在其他细胞类型中的作用形成鲜明对比，将其确定为动脉粥样硬化斑块生长的重要驱动因素，并表明针对控制这种疾病的细胞类型特异性治疗干预的潜力。
