Integrated Single-Cell and Spatial Analysis Reveals a Metabolic-Immune Axis Driving Aortic Dissection

Area of Science:

• Cardiovascular Biology
• Translational Medicine
• Genomics

Background:

• Mechanisms of aortic dissection (AD) are not fully understood due to limited patient cohorts.
• Existing single-cell studies provide some insight into diseased aortas.

Purpose of the Study:

• To create a comprehensive cellular-molecular atlas of the thoracic aorta.
• To elucidate the cellular and molecular mechanisms driving aortic dissection.

Main Methods:

• Integration of single-cell and spatial transcriptomic data from 110 thoracic aortic samples.
• Analysis of samples from control, aneurysm, and dissection groups (80 individuals).
• Identification of cell subsets and molecular pathways involved in AD pathogenesis.

Main Results:

• A novel elastin-rich fibroblast subset (Fibro_C1_FBN1+) declines with age and is depleted in AD, increasing aortic vulnerability.
• Vascular smooth muscle cells (vSMCs) reprogram under hypoxia (ENO1-driven), lose contractility, and promote inflammation and extracellular matrix degradation.
• ENO1 knockdown in vitro and in vivo reduced vSMC switching, macrophage inflammation, and slowed AD progression.

Conclusions:

• A stromal-immune axis involving fibroblasts and vSMCs plays a critical role in AD.
• Fibroblast depletion and vSMC reprogramming contribute to aortic wall vulnerability and dissection risk.
• Targeting ENO1 and the identified stromal-immune interactions presents potential therapeutic avenues for AD.