Departamento de Epidemiología, Aterotrombosis e Imagen, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1248-56. doi: 10.1161/ATVBAHA.112.300539. Epub 2013 Feb 28.
Different vascular beds show differing susceptibility to the development of atherosclerosis, but the molecular mechanisms underlying these differences are incompletely understood. This study aims to identify factors that contribute to the phenotypic heterogeneity of distinct regions of the adult vasculature.
High-throughput mRNA profiling in adult mice reveals higher expression of the homeobox paralogous genes 6 to 10 (Hox6-10) in the athero-resistant thoracic aorta (TA) than in the athero-susceptible aortic arch (AA). Higher homeobox gene expression also occurs in rat and porcine TA, and is maintained in primary smooth muscle cells isolated from TA (TA-SMCs) compared with cells from AA (AA-SMCs). This region-specific homeobox gene expression pattern is also observed in human embryonic stem cells differentiated into neuroectoderm-SMCs and paraxial mesoderm-SMCs, which give rise to AA-SMCs and TA-SMCs, respectively. We also find that, compared with AA and AA-SMCs, TA and TA-SMCs have lower activity of the proinflammatory and proatherogenic nuclear factor-κB (NF-κB) and lower expression of NF-κB target genes, at least in part attributable to HOXA9-dependent inhibition. Conversely, NF-κB inhibits HOXA9 promoter activity and mRNA expression in SMCs.
Our findings support a model of Hox6-10-specified positional identity in the adult vasculature that is established by embryonic cues independently of environmental factors and is conserved in different mammalian species. Differential homeobox gene expression contributes to maintaining phenotypic differences between SMCs from athero-resistant and athero-susceptible regions, at least in part through feedback regulatory mechanisms involving inflammatory mediators, for example, reciprocal inhibition between HOXA9 and NF-κB.
不同的血管床对动脉粥样硬化的易感性不同，但这些差异的分子机制尚不完全清楚。本研究旨在确定导致成年血管不同区域表型异质性的因素。
在成年小鼠中进行高通量 mRNA 谱分析显示，在抗动脉粥样硬化的胸主动脉（TA）中，同源盒基因 6-10（Hox6-10）的表达高于易发生动脉粥样硬化的主动脉弓（AA）。在大鼠和猪的 TA 中也出现了更高的同源盒基因表达，并且在从 TA 分离的平滑肌细胞（TA-SMCs）中保持，而在 AA 中（AA-SMCs）则没有。这种区域特异性的同源盒基因表达模式也在人类胚胎干细胞分化为神经外胚层-SMCs 和轴旁中胚层-SMCs 中观察到，分别产生 AA-SMCs 和 TA-SMCs。我们还发现，与 AA 和 AA-SMCs 相比，TA 和 TA-SMCs 的促炎和促动脉粥样硬化核因子-κB（NF-κB）活性较低，NF-κB 靶基因的表达也较低，至少部分归因于 HOXA9 依赖性抑制。相反，NF-κB 抑制 SMC 中 HOXA9 启动子活性和 mRNA 表达。
我们的研究结果支持了一种模型，即 Hox6-10 特异性在成年血管中的位置身份是由胚胎线索建立的，独立于环境因素，并且在不同的哺乳动物物种中是保守的。差异的同源盒基因表达有助于维持抗动脉粥样硬化和易发生动脉粥样硬化区域的 SMC 之间的表型差异，至少部分通过涉及炎症介质的反馈调节机制，例如 HOXA9 和 NF-κB 之间的相互抑制。
