SM22a-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-1a (PGC-1a) was measured in PVAT of aged mice and human aneurysm samples. Loss- and gain-of-function approaches were employed to investigate the role of SM22a-lineage PVSCs-derived PGC-1a in aneurysm development. Molecular mechanisms were explored through transcriptome and functional studies in young and aged mice, SM22aCre; Rosa26RFP/+; PGC1af/f and SM22aCre; Rosa26RFP/+ mice with angiotensin II (AngII)- and DOCA/salt- induced AAA models. Results: SM22a+ 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 SM22a-lineage PVSCs and led to reduced PGC-1a level. PGC1a downregulation in PVAT was observed in both mice AAA models and human aneurysm lesions. In mice with SM22a-driven PGC-1a-deletion AngII induced AAA formation was accompanied by PVSC-to-myofibroblast differentiation. in vitro PGC1a-knockdown suppressed nuclear YAP signaling, reducing adipocyte differentiation, while increasing MMP2-secreting myofibroblasts. Furthermore, PGC-1a overexpression in aged mice or administration of the YAP signaling inhibitor Verteporfin in SM22aCre; Rosa26RFP/+; PGC1af/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-1a deficiency in SM22a-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. Overall design: Perivascular stromal cells were isolated from pervascular adipose tissue of young and old mice and analyzed using scRNA-seq.