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

Ionic signaling in smooth muscle cells (SMCs) is critical for vascular homeostasis. In this study, we untangled the role of the bifunctional TRPM7 channel kinase (chanzyme) in abdominal aortic aneurysm (AAA) pathogenesis. Comparing SMC-specific, macrophage-specific and endothelial cell-specific Trpm7 knockout, we revealed that SMC-specific Trpm7 deficiency protected mice from AAA in two distinct preclinical models of the disease. We showed that the TRPM7 channel activity increased the Ca²⁺ and Zn²⁺ influx and the Ca²⁺/calcineurin/CRTC2/CREB-dependent and Zn²⁺/MTF1-dependent Mmp2 transcription. Repurposing the clinical drug FTY720 to prevent and treat AAA resulted in improved aortic phenotypes through inhibition of TRPM7 channel activity. This study highlights the ionic mechanisms underlying AAA, identifies TRPM7 as a potential therapeutic target and suggests that blocking TRPM7 channels could be a viable strategy for treating AAA.