Aims β3-AR (β3-adrenergic receptor) is essential for cardiovascular homeostasis 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. Methods and Results 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 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 (LNs) 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 lymphatic endothelial cells (LECs), which was abrogated by the silencing of VEGF-C in adipocytes. Conclusions 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.

中文翻译：

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米拉贝隆激活 β3-AR 通过促进血管周围脂肪组织中的淋巴管生成来预防主动脉夹层/动脉瘤


目的 β3-AR（β3-肾上腺素能受体）通过调节脂肪组织功能对于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。在这里，我们的目的是研究 AD/AA 中 β3-AR 激活介导的 PVAT 功能。方法与结果收集胸主动脉夹层（TAD）患者的主动脉，检测PVAT中β3-AR的表达。用血管紧张素 II (AngII) 诱导 ApoE-/- 和 β-氨基丙腈单富马酸酯 (BAPN) 治疗的 C57BL/6 小鼠以模拟 AD/AA，随后接受安慰剂或米拉贝隆（一种 β3-AR 激动剂）。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可显着阻止AngII诱导的小鼠AD/AA形成。对 PVAT 脂肪细胞的 RNA 测序分析显示，米拉贝隆治疗的小鼠中淋巴管生成因子 VEGF-C 显着增加。一致地，米拉贝隆治疗后的 PVAT 中发现淋巴管生成增强。从机制上讲，米拉贝隆治疗小鼠的 PVAT 中 CD4+/CD8+ T 细胞和 CD11c+ 细胞的数量减少，但邻近引流淋巴结 (LN) 的数量增加，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，腺相关病毒系统对脂肪细胞特异性 VEGF-C 的敲低抑制了淋巴管生成，并加剧了 PVAT 中的炎症细胞浸润，最终消除了米拉贝隆对 AD/AA 的保护作用。 此外，源自米拉贝隆处理的脂肪细胞的条件培养基激活了淋巴内皮细胞（LEC）的增殖和管形成，而脂肪细胞中 VEGF-C 的沉默可消除这种增殖和管形成。结论 我们的研究结果说明了米拉贝隆激活 β3-AR 对 AD/AA 的治疗潜力，它通过增加脂肪细胞来源的 VEGF-C 促进淋巴管生成，从而改善 PVAT 炎症。