Activation of β3-AR by mirabegron prevents aortic dissection/aneurysm by promoting lymphangiogenesis in perivascular adipose tissue

IF 10.2 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Ze-Bei Zhang, Yu-Wen Cheng, Lian Xu, Jia-Qi Li, Xin Pan, Min Zhu, Xiao-Hui Chen, Ai-Jun Sun, Jing-Rong Lin, Ping-Jin Gao
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引用次数: 0

Abstract

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.
米拉贝琼通过促进血管周围脂肪组织的淋巴管生成来激活β3-AR,从而预防主动脉夹层/动脉瘤的发生
目的 β3-AR(β3-肾上腺素能受体)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 AD/AA 中β3-AR 激活介导的 PVAT 功能。方法和结果 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)诱导载脂蛋白E-/-和β-氨基丙腈单富马酸盐(BAPN)处理的C57BL/6小鼠以模拟AD/AA,随后接受安慰剂或米拉贝琼(一种β3-AR激动剂)。结果表明,TAD 患者和 AD/AA 小鼠 PVAT 中的β3-AR 上调。此外,米拉贝琼对β3-AR的激活能显著预防AngII诱导的小鼠AD/AA的形成。PVAT脂肪细胞的RNA序列分析显示,米拉贝琼治疗的小鼠淋巴管生成因子VEGF-C明显增加。同样,经米拉贝琼治疗后,PVAT 中的淋巴管生成也得到了增强。从机理上讲,米拉贝琼处理的小鼠 PVAT 中 CD4+/CD8+ T 细胞和 CD11c+ 细胞的数量减少,但相邻引流淋巴结(LN)的数量增加,这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,通过腺相关病毒系统敲除脂肪细胞特异性 VEGF-C 抑制了淋巴管生成,加剧了 PVAT 中炎性细胞的浸润,最终取消了米拉贝琼对 AD/AA 的保护作用。此外,从米拉贝琼处理过的脂肪细胞中提取的条件培养基激活了淋巴内皮细胞(LECs)的增殖和管形成,而脂肪细胞中 VEGF-C 的沉默抑制了这一作用。结论 我们的研究结果表明了米拉贝琼激活β3-AR对AD/AA的治疗潜力,它通过增加脂肪细胞衍生的VEGF-C促进淋巴管生成,从而改善了PVAT炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cardiovascular Research
Cardiovascular Research 医学-心血管系统
CiteScore
21.50
自引率
3.70%
发文量
547
审稿时长
1 months
期刊介绍: Cardiovascular Research Journal Overview: International journal of the European Society of Cardiology Focuses on basic and translational research in cardiology and cardiovascular biology Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects Submission Criteria: Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels Accepts clinical proof-of-concept and translational studies Manuscripts expected to provide significant contribution to cardiovascular biology and diseases
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