Zhang Ze-Bei, Cheng Yu-Wen, Xu Lian, Li Jia-Qi, Pan Xin, Zhu Min, Chen Xiao-Hui, Sun Ai-Jun, Lin Jing-Rong, Gao Ping-Jin
Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin, 2 Road, Shanghai 200025, China.
Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cardiovasc Res. 2024 Dec 31;120(17):2307-2319. doi: 10.1093/cvr/cvae213.
β3-Adrenergic receptor (β3-AR) is essential for cardiovascular homoeostasis through regulating adipose tissue function. Perivascular adipose tissue (PVAT) has been implicated in the pathogenesis of aortic dissection and aneurysm (AD/AA). Here, we aim to investigate β3-AR activation-mediated PVAT function in AD/AA.
Aortas from patients with thoracic aortic dissection (TAD) were collected to detect β3-AR expression in PVAT. ApoE-/- and β-aminopropionitrile monofumarate (BAPN)-treated C57BL/6 mice were induced with Angiotensin II (AngII) to simulate AD/AA and subsequently received either placebo or mirabegron, a β3-AR agonist. The results demonstrated an up-regulation of β3-AR in PVAT of TAD patients and AD/AA mice. Moreover, activation of β3-AR by mirabegron significantly prevented AngII-induced AD/AA formation in mice. RNA-sequencing analysis of adipocytes from PVAT revealed a notable increase of the lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), in mirabegron-treated mice. Consistently, enhanced lymphangiogenesis was found in PVAT with mirabegron treatment. Mechanistically, the number of CD4+/CD8+ T cells and CD11c+ cells was reduced in PVAT but increased in adjacent draining lymph nodes of mirabegron-treated mice, indicating the improved draining and clearance of inflammatory cells in PVAT by lymphangiogenesis. Importantly, adipocyte-specific VEGF-C knockdown by the adeno-associated virus system restrained lymphangiogenesis and exacerbated inflammatory cell infiltration in PVAT, which ultimately abolished the protection of mirabegron on AD/AA. In addition, the conditional medium derived from mirabegron-treated adipocytes activated the proliferation and tube formation of LECs, which was abrogated by the silencing of VEGF-C in adipocytes.
Our findings illustrated the therapeutic potential of β3-AR activation by mirabegron on AD/AA, which promoted lymphangiogenesis by increasing adipocyte-derived VEGF-C and, therefore, ameliorated PVAT inflammation.
β3-肾上腺素能受体（β3-AR）通过调节脂肪组织功能对心血管稳态至关重要。血管周围脂肪组织（PVAT）与主动脉夹层和动脉瘤（AD/AA）的发病机制有关。在此，我们旨在研究β3-AR激活介导的PVAT在AD/AA中的功能。
收集胸主动脉夹层（TAD）患者的主动脉，检测PVAT中β3-AR的表达。用载脂蛋白E基因敲除（ApoE-/-）和β-氨基丙腈富马酸盐（BAPN）处理的C57BL/6小鼠用血管紧张素II（AngII）诱导以模拟AD/AA，随后接受安慰剂或β3-AR激动剂米拉贝隆。结果表明，TAD患者和AD/AA小鼠的PVAT中β3-AR上调。此外，米拉贝隆激活β3-AR可显著预防AngII诱导的小鼠AD/AA形成。对PVAT脂肪细胞的RNA测序分析显示，米拉贝隆处理的小鼠中淋巴管生成因子血管内皮生长因子C（VEGF-C）显著增加。一致地，米拉贝隆处理的PVAT中淋巴管生成增强。机制上，米拉贝隆处理的小鼠PVAT中CD4+/CD8+ T细胞和CD11c+细胞数量减少，但在相邻引流淋巴结中增加，表明淋巴管生成改善了PVAT中炎症细胞的引流和清除。重要的是，腺相关病毒系统敲低脂肪细胞特异性VEGF-C可抑制淋巴管生成并加剧PVAT中的炎症细胞浸润，最终消除米拉贝隆对AD/AA的保护作用。此外，米拉贝隆处理的脂肪细胞条件培养基激活淋巴管内皮细胞（LECs）的增殖和管腔形成，而脂肪细胞中VEGF-C沉默可消除这种作用。
我们的研究结果表明米拉贝隆激活β3-AR对AD/AA具有治疗潜力，其通过增加脂肪细胞衍生的VEGF-C促进淋巴管生成，从而改善PVAT炎症。
