Integrative Omics Identifies Candidate Plasma Biomarkers and Cellular Targets Associated with Thoracic Aortic Aneurysm

Thoracic aortic aneurysm (TAA) results from aortic wall weakening and enlargement, leading to severe complications like rupture and dissection. However, the full cellular landscape of TAA tissue and its role in disease pathogenesis remain incompletely understood, and reliable blood-based biomarkers for assessment are limited. We performed single-cell RNA sequencing on 17 aortic tissue samples from 10 patients undergoing reparative TAA surgery. Cells were clustered into distinct subsets and integrated with publicly available datasets. Additionally, tomographic aortic imaging and plasma proteomics were conducted for 11 participants to identify novel TAA severity candidate biomarkers. We identified 25 distinct cellular subsets, including macrophages, endothelial cells, vascular smooth muscle cells (VSMCs), and fibroblasts, highlighting their specialized roles in the vascular wall. Integrative analysis with two public datasets revealed differences in cellular proportions and transcriptomic profiles, underscoring TAA tissue heterogeneity. Notably, genome-wide association study candidate genes, such as JUN and TPM3, were upregulated and showed cell type-specific expression. Combining clinical imaging with plasma proteomics, we identified several candidate plasma biomarkers positively correlated with aortic diameter. Validation using UK Biobank data confirmed that only FGF-23 was significantly upregulated in TAA. Furthermore, FGFR1, the receptor for FGF-23, was specifically expressed on VSMCs and fibroblasts in both human and murine models. Our study provides an integrative analysis of TAA tissue, challenging assumptions about its compositional and transcriptional changes. Importantly, we uncovered an unrecognized FGF-23:FGFR1 signaling pathway in VSMCs and fibroblasts, which may drive disease progression.