SM22α-Lineage Perivascular Stromal Cells Contribute to Abdominal Aortic Aneurysm

Abstract

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 (AAAs). Yet, the mechanisms underlying PVAT plasticity in aneurysm pathogenesis remain elusive.

Methods: Single-cell RNA sequencing was performed on perivascular stromal cells (PVSCs) from young (2- to 3-month-old) and aged (18- to 20-month-old) mice. The expression of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α) was measured in PVAT of aged mice and human aneurysm samples. Loss- and gain-of-function approaches were used to investigate the role of SM22α (Smooth Muscle 22-Alpha)-lineage PVSCs-derived PGC-1α in aneurysm development. Molecular mechanisms were explored through transcriptome and functional studies in young and aged mice, SM22α^Cre; Rosa26^RFP/+; PGC1α^f/f and SM22α^Cre; Rosa26^RFP/+ mice with Ang II (angiotensin II)-induced and deoxycorticosterone acetate/salt-induced AAA models.

Results: SM22α⁺ cells accumulated in PVAT of Ang II-treated aged mice and patients with aortic aneurysms. Single-cell RNA sequencing analysis revealed that aging disrupted the differentiation potential of SM22α-lineage PVSCs and led to reduced PGC-1α levels. PGC1α downregulation in PVAT was observed in both mouse AAA models and human aneurysm lesions. In mice with SM22α-driven PGC-1α deletion, Ang II-induced AAA formation was accompanied by perivascular stromal cell-to-myofibroblast differentiation. In vitro PGC1α knockdown suppressed nuclear YAP (Yes-associated protein) signaling, reducing adipocyte differentiation, while increasing MMP2 (matrix metalloproteinase 2)-secreting myofibroblasts. Furthermore, PGC-1α overexpression in aged mice or administration of the YAP signaling inhibitor verteporfin in SM22α^Cre; Rosa26^RFP/+; PGC1α^f/f mice restored PVAT function and conferred protection against AAA formation. Last, we used the radiomics analysis to noninvasively evaluate PVAT in the context of AAA severity in humans.

Conclusions: PGC-1α deficiency in SM22α-lineage PVSCs disrupts the balance between adipogenic and myofibrogenic differentiation through regulating YAP signaling, ultimately promoting AAA development. Radiomics assessment may present a promising noninvasive approach for PVAT evaluation in aneurysms, offering valuable potential for clinical research.

Keywords: adipose tissue; aging; aortic aneurysm; aortic aneurysm, abdominal; single-cell gene expression analysis.