Tgfbr2 deficiency promotes mitochondrial dysfunction of vascular smooth muscle cells in thoracic aortic aneurysms and dissections.

Mitochondrial dysregulation promotes vascular destabilization through modulation of the phenotypic plasticity of vascular smooth muscle cells (VSMCs) in thoracic aortic aneurysms and dissections (TAADs). Canonical transforming growth factor-β (TGF-β) signaling, another pivotal pathway in TAADs, also controls VSMC homeostasis, yet the mechanistic interplay between these two axes is unclear. We aimed to determine whether, and how, dysregulated TGF-β signaling directly precipitates mitochondrial injury that drives TAADs progression. Herein, we systematically characterized the regulatory nexus between TGF-β signaling and mitochondrial function during TAADs progression. Single-cell transcriptomic profiling revealed significant correlation between mitochondrial dysfunction and TGF-β pathway dysregulation in TAADs specimens. Using conditional Tgfbr2 knockout mice with VSMC-specific targeting, we provide compelling evidence that dysregulated TGF-β signaling mediates mitochondrial impairment through intricate molecular crosstalk. Bulk RNA sequencing and untargeted metabolomics established a definitive causal relationship between mitochondrial dysfunction and aortic degeneration severity in VSMC-specific Tgfbr2-deficient mice. Pseudo-temporal trajectory analysis identified mitochondrial respiratory complex IV as a critical downstream effector of TGF-β-mediated mitochondrial regulation. Western blot analyses demonstrated that VSMC-specific Tgfbr2 ablation significantly diminished the expression of complex IV regulatory proteins, exhibiting linear correlation with vascular injury severity. Our findings establish a paradigmatic shift in TAADs pathophysiology from unidirectional mechanisms toward integrated multi-pathway networks, providing a robust theoretical framework for developing synergistic therapeutic interventions targeting the mitochondrial-TGF-β regulatory axis.