Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, South Parks Road, Oxford OX1 3PT, UK.
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, South Parks Road, Oxford OX1 3PT, UK; Institute of Developmental and Regenerative Medicine, University of Oxford, IMS-Tetsuya Nakamura Building, Old Road Campus, Oxford OX3 7TY, UK.
Int Immunopharmacol. 2023 Feb;115:109702. doi: 10.1016/j.intimp.2023.109702. Epub 2023 Jan 20.
Atherosclerosis is a progressive, degenerative vascular disease and a leading cause of morbidity and mortality. In response to endothelial damage, platelet derived growth factor (PDGF)-BB induced phenotypic modulation of medial smooth muscle cells (VSMCs) promotes atherosclerotic lesion formation and destabilisation of the vessel wall. VSMC sensitivity to PDGF-BB is determined by endocytosis of Low density lipoprotein receptor related protein 1 (LRP1)-PDGFR β complexes to balance receptor recycling with lysosomal degradation. Consequently, LRP1 is implicated in various arterial diseases. Having identified Tβ4 as a regulator of LRP1-mediated endocytosis to protect against aortic aneurysm, we sought to determine whether Tβ4 may additionally function to protect against atherosclerosis, by regulating LRP1-mediated growth factor signalling. By single cell transcriptomic analysis, Tmsb4x, encoding Tβ4, strongly correlated with contractile gene expression and was significantly down-regulated in cells that adopted a modulated phenotype in atherosclerosis. We assessed susceptibility to atherosclerosis of global Tβ4 knockout mice using the ApoE hypercholesterolaemia model. Inflammation, elastin integrity, VSMC phenotype and signalling were analysed in the aortic root and descending aorta. Tβ4KO; ApoE mice develop larger atherosclerotic plaques than control mice, with medial layer degeneration characterised by accelerated VSMC phenotypic modulation. Defects in Tβ4KO; ApoE mice phenocopied those in VSMC-specific LRP1 nulls and, moreover, were underpinned by hyperactivated LRP1-PDGFRβ signalling. We identify an atheroprotective role for endogenous Tβ4 in maintaining differentiated VSMC phenotype via LRP1-mediated PDGFRβ signalling.
动脉粥样硬化是一种进行性、退行性血管疾病，也是发病率和死亡率的主要原因。在血管内皮损伤后，血小板衍生生长因子（PDGF）-BB 诱导的中膜平滑肌细胞（VSMCs）表型调节促进动脉粥样硬化病变的形成和血管壁的不稳定。VSMC 对 PDGF-BB 的敏感性取决于低密度脂蛋白受体相关蛋白 1（LRP1）-PDGFRβ 复合物的内吞作用，以平衡受体的再循环与溶酶体降解。因此，LRP1 与各种动脉疾病有关。我们已经确定 Tβ4 是 LRP1 介导的内吞作用的调节剂，可防止主动脉瘤，我们试图确定 Tβ4 是否可以通过调节 LRP1 介导的生长因子信号来预防动脉粥样硬化，通过调节 LRP1 介导的生长因子信号。通过单细胞转录组分析，编码 Tβ4 的 Tmsb4x 与收缩基因表达强烈相关，并且在动脉粥样硬化中采用调节表型的细胞中显著下调。我们使用 ApoE 高脂血症模型评估了全球 Tβ4 敲除小鼠对动脉粥样硬化的易感性。在主动脉根部和降主动脉中分析了炎症、弹性蛋白完整性、VSMC 表型和信号转导。Tβ4KO;ApoE 小鼠比对照小鼠形成更大的动脉粥样硬化斑块，中层层退化的特征是 VSMC 表型调节加速。Tβ4KO;ApoE 小鼠的缺陷与 VSMC 特异性 LRP1 缺失的表型相似，而且，这是由 LRP1-PDGFRβ 信号的过度激活所支撑的。我们确定了内源性 Tβ4 通过 LRP1 介导的 PDGFRβ 信号在维持分化的 VSMC 表型方面的抗动脉粥样硬化作用。
