Abstract
Obesity is a significant risk factor for thoracic aortic dissection (TAD), as supported by UK Biobank data showing obese individuals have a higher risk of TAD. The study investigates leptin, a hormone elevated in obesity, and finds that hyperleptinemia is common in TAD patients, suggesting its role in disease pathogenesis. Using leptin-knockout mice, it is demonstrated that exogenous leptin exacerbates TAD by promoting phenotypic transitions in vascular smooth muscle cells (VSMCs). These adverse effects are reversible with pharmacologic leptin blockade, indicating potential therapeutic benefits. Single-cell RNA sequencing reveals a novel smooth muscle cells (SMC) cluster, Nrip2+, in the aorta, with a distinct contractile gene profile. Increased Nrip2+ VSMCs are linked to enhanced mitochondrial energy metabolism. Elevated Nrip2+ VSMCs inhibit the leptin-induced transition from a contractile to a synthetic phenotype, reducing TAD incidence. The findings suggest that high blood leptin levels contribute to the increased TAD risk in obese individuals by suppressing Nrip2+ SMCs, leading to abnormal mitochondrial metabolism and VSMC phenotypic transitions. Thus, targeting leptin to boost Nrip2+ VSMC metabolic activity is a promising strategy for TAD prevention and treatment.