The TRPM7 chanzyme in smooth muscle cells drives abdominal aortic aneurysm in mice.

Summary

Using cell type–specific knockouts across two AAA mouse models, the study shows that TRPM7 chanzyme activity in vascular smooth muscle cells drives aneurysm formation, promoting VSMC phenotypic switching, inflammation, and matrix degradation. SMC-specific Trpm7 deletion was protective, nominating TRPM7 as a therapeutic target.

Key Findings

• SMC-specific Trpm7 knockout protected mice from AAA in two distinct preclinical models.
• TRPM7 channel activity promoted Ca2+-dependent signaling, VSMC reprogramming, inflammation, and extracellular matrix degradation.
• Cell type–specific comparisons showed the pathogenic role was specific to smooth muscle cells, not macrophages or endothelial cells.

Clinical Implications

While preclinical, targeting TRPM7 activity in VSMCs could emerge as a disease-modifying approach to slow or prevent AAA growth pending safety and translational studies.

Limitations

• Preclinical mouse models; human validation and safety of TRPM7 modulation are unknown
• Potential off-target effects of TRPM7 inhibition and systemic consequences were not addressed

Future Directions

Validate TRPM7 pathways in human AAA tissues, develop selective modulators, assess pharmacodynamics and safety, and test efficacy in large-animal models.