Objective: 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.
Approach and results: 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.
Conclusion: 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.
Keywords: NF-κB; atherosclerosis; homeobox; phenotypic diversity; smooth muscle cell.