SM22α-lineage stromal cells in perivascular adipose tissue contribute to abdominal aortic aneurysm

Background: Perivascular adipose tissue (PVAT) is a key regulator of vascular dysfunction. Impairment of PVAT phenotypic plasticity with aging may play a role in vascular pathology including abdominal aortic aneurysms (AAA). Yet, the mechanisms underlying PVAT plasticity in aneurysm pathogenesis remain elusive. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on perivascular stromal cells (PVSCs) from young (2-3-month-old) and aged (18-20-month-old) mice. The expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) was measured in PVAT of aged mice and human aneurysm samples. Loss- and gain-of-function approaches were employed to investigate the role of SM22α-lineage PVSCs-derived PGC-1α in aneurysm development. Molecular mechanisms were explored through transcriptome and functional studies in young and aged mice, SM22αCre; Rosa26RFP/+; PGC1αf/f and SM22αCre; Rosa26RFP/+ mice with angiotensin II (AngII)- and DOCA/salt- induced AAA models. Results: SM22α+ cells accumulated in PVAT of angiotensin II-treated aged mice and patients with aortic aneurysms. scRNA-seq analysis revealed that aging disrupted the differentiation potential of SM22α-lineage PVSCs and led to reduced PGC-1α level. PGC1α downregulation in PVAT was observed in both mice AAA models and human aneurysm lesions. In mice with SM22α-driven PGC-1α-deletion AngII induced AAA formation was accompanied by PVSC-to-myofibroblast differentiation. in vitro PGC1α-knockdown suppressed nuclear YAP signaling, reducing adipocyte differentiation, while increasing MMP2-secreting myofibroblasts. Furthermore, PGC-1α overexpression in aged mice or administration of the YAP signaling inhibitor Verteporfin in SM22αCre; Rosa26RFP/+; PGC1αf/f mice restored PVAT function and conferred protection against aneurysm formation. Lastly, we employed the radiomics analysis to non-invasively evaluate PVAT in the context of AAA severity in humans. Conclusions: PGC-1α deficiency in SM22α-lineage stromal cells disrupts the balance between adipogenic and myofibrogenic differentiation through regulating the YAP signaling, ultimately promoting aneurysm development. Radiomics assessment may present a promising noninvasive approach for PVAT evaluation in aneurysms, offering valuable potential for clinical research. Perivascular stromal cells were isolated from pervascular adipose tissue of young and old mice and analyzed using scRNA-seq.