Transcription regulation by TBX18 in smooth muscle cells is essential for normal aortic development and homeostasis.

AIMS: This study investigated whether TBX18, a transcription factor known for its critical roles in cardiovascular and urogenital development, but never previously studied in the context of the aorta, contributes to the normal development and homeostasis of this major artery. METHODS AND RESULTS: Histological analyses revealed Tbx18 expression in smooth muscle cells (SMCs) of the adult and embryonic aorta. Following this observation, transgenic mouse models were used to promote ablation of Tbx18 in SMCs from early embryogenesis or in adulthood. Phenotypes were assessed by quantitative imaging and histological analyses. Embryonic conditional ablation of Tbx18 resulted in severe aortic malformations and lethality, whereas adult ablation resulted in milder phenotypes. However, when adult Tbx18 ablation was combined with a Marfan-causing mutation, it promoted degradation of aortic ultrastructure, aortic root dilation, and lethality. Multiomics analyses at the transcriptomic and translatomic levels revealed up-regulation of immediate early genes encoding critical transcription factors such as EGR1, FOS, and JUNB in SMCs from Marfan aortae, a response further exacerbated by concomitant ablation of Tbx18. ChIP-seq in primary human aortic SMCs revealed that TBX18 directly binds to several of the genes that were misexpressed in mutant aortae, suggesting direct regulation. Finally, transcriptomic and histological analyses of human patient samples revealed that TBX18 expression was down-regulated in aneurysms, with the extent of down-regulation correlating with lesion severity. CONCLUSION: These results demonstrate that TBX18 in SMCs is essential not only for normal aortic development, but also for preventing gene expression programmes linked to adverse remodelling in adulthood. These findings enhance our understanding of the function of this transcription factor and of molecular mechanisms underlying aneurysm formation, a pathology responsible for a significant number of fatalities in developed countries.