Pan Xiaoxi, Zhang Run, Lu Bingling, Chen Siyuan, Chen Hongjin, Li Mengyao, Qin Le, Song Zhiyun, Yang Yi, Wang Zhe, Yan Fuhua, Sun Aijun, Wu Fang, Zhang Lichi, Wang Jiguang, Guzik Tomasz J, Gao Pingjin
Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension (X.P., R.Z., S.C., H.C., M.L., J.W., P.G.), Shanghai Jiao Tong University School of Medicine, China.
School of Biomedical Engineering, Shanghai Jiao Tong University, China (B.L., Z.S., L.Z.).
Circ Res. 2025 Jun 20;137(1):4-22. doi: 10.1161/CIRCRESAHA.124.325750. Epub 2025 May 15.
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; Rosa26; PGC1α and SM22α; Rosa26 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; Rosa26; PGC1α 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.
背景：血管周围脂肪组织（PVAT）是血管功能障碍的关键调节因子。随着年龄增长，PVAT表型可塑性受损可能在包括腹主动脉瘤（AAA）在内的血管病变中起作用。然而，PVAT可塑性在动脉瘤发病机制中的潜在机制仍不清楚。 方法：对年轻（2至3个月大）和老年（18至20个月大）小鼠的血管周围基质细胞（PVSC）进行单细胞RNA测序。在老年小鼠和人类动脉瘤样本的PVAT中测量过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）的表达。采用功能丧失和功能获得方法研究平滑肌22α（SM22α）谱系PVSC衍生的PGC-1α在动脉瘤发展中的作用。通过对年轻和老年小鼠、SM22α;Rosa26;PGC1α和SM22α;Rosa26小鼠进行血管紧张素II（Ang II）诱导和醋酸脱氧皮质酮/盐诱导的AAA模型的转录组和功能研究，探索分子机制。 结果：在Ang II处理的老年小鼠和主动脉瘤患者的PVAT中，SM22α细胞积累。单细胞RNA测序分析显示，衰老破坏了SM2α谱系PVSC的分化潜能，导致PGC-1α水平降低。在小鼠AAA模型和人类动脉瘤病变中均观察到PVAT中PGC1α下调。在SM22α驱动的PGC-1α缺失的小鼠中，Ang II诱导的AAA形成伴随着血管周围基质细胞向肌成纤维细胞的分化。体外PGC1α敲低抑制了核Yes相关蛋白（YAP）信号传导，减少了脂肪细胞分化，同时增加了分泌基质金属蛋白酶2（MMP2）的肌成纤维细胞。此外，在老年小鼠中过表达PGC-1α或在SM22α;Rosa26;PGC1α小鼠中给予YAP信号抑制剂维替泊芬可恢复PVAT功能，并对AAA形成具有保护作用。最后，我们使用放射组学分析在人类AAA严重程度的背景下对PVAT进行无创评估。 结论：SM22α谱系PVSC中的PGC-1α缺乏通过调节YAP信号传导破坏了脂肪生成和肌成纤维细胞分化之间的平衡，最终促进了AAA的发展。放射组学评估可能是一种有前途的无创评估动脉瘤中PVAT的方法，为临床研究提供了有价值的潜力。
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