Aneurysms of the aorta occur when the wall of the aorta loses its stability and expands. If such an expansion remains undetected, it can lead to life-threatening complications, such as a tear or split in the vessel wall. The risks are particularly high if a hereditary connective tissue disorder such as Marfan syndrome is already present. In light of this, it is important to understand which molecular factors keep the aorta stable. An international study now shows that the gene regulator TBX18 plays a crucial role in this process.
Why TBX18 is important
The aorta is constantly exposed to high pressure fluctuations. To remain stable, its muscle cells must maintain a balanced gene programme. The new study shows that TBX18 coordinates these programmes. If TBX18 is switched off in a mouse model, malformations of the aorta occur. In adult animals, the vessel wall becomes susceptible to damage, especially if there is already stress, as in the case of a Marfan mutation.
‘TBX18 acts as a stability factor for the vessel wall,’ says Prof. Stefanie Dimmeler from Frankfurt University Hospital and the German Centre for Cardiovascular Research (DZHK). ‘If it is missing, the cells react hypersensitively to stress.’
What happens inside the cells
The researchers discovered that TBX18 prevents certain stress genes from activating, which would otherwise trigger remodelling processes in the vessel wall. These include genes such as EGR1, FOS and JUNB, which become active in the early stages of many aneurysms.
If TBX18 is missing, these genes are activated. The muscle cells change, begin to remodel tissue more rapidly and thus contribute to the weakening of the aortic wall. Another finding: the protein thrombospondin-1 (THBS1), which can support remodelling processes in the vessel wall, increases significantly without TBX18.
Results also confirmed in humans
The researchers found the same pattern in tissue samples from patients with aortic aneurysms in the chest or abdominal area: TBX18 was significantly reduced, and the more pronounced the aneurysm, the greater the reduction.
‘The data from humans matches exactly with the experiments in the mouse model,’ said first author Dr Nuno Guimarães-Camboa. ‘This shows that TBX18 plays a central role in protecting the aorta.’
Outlook
The results show that TBX18 controls key switching points that are activated early in the aneurysm process, thus offering starting points for new therapeutic strategies. Since these programmes are triggered before structural damage occurs, targeted interventions in these signalling pathways could help slow down the development or progression of aneurysms. The work provides concrete molecular target structures that can be further developed in pharmacological or biological approaches to protect patients in the long term.
Original publication:
Mukherjee, Debanjan et al. “Transcription regulation by TBX18 in smooth muscle cells is essential for normal aortic development and homeostasis.” Cardiovascular research vol. 121,15 (2025): 2419-2431. doi:10.1093/cvr/cvaf201
