Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA.
Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA.
Metabolism. 2018 Aug;85:76-89. doi: 10.1016/j.metabol.2018.03.002. Epub 2018 Mar 9.
Accumulation of multiple subtypes of immune cells in perivascular adipose tissue (PVAT) has been proposed to cause vascular inflammation and dysfunction in type 2 diabetes (T2DM). This study was designed to investigate specific roles for dendritic cells in PVAT in the development of vascular inflammation and impaired PVAT-mediated vasorelaxation in T2DM.
Studies were performed using db/db mice (model of T2DM) and their Db heterozygote (DbHET), lean and normoglycemic controls. Dendritic cell depletion was performed by cross-breeding DbHet with Flt3l (null for ligand for FMS-kinase tyrosine kinase) mice. Using PCR, it was found that the majority of dendritic cells (CD11c) were located in PVAT rather than the vascular wall. Flow cytometry similarly showed greater dendritic cell accumulation in adipose tissue from db/db mice than DbHET controls. Adipose tissue from db/db mice displayed increased mRNA levels of proinflammatory cytokines TNF-α and IL-6 and decreased mRNA levels of the anti-inflammatory mediator adiponectin, compared to DbHET mice. Depletion of dendritic cells in db/db (confirmed by flow cytometry) reduced TNF-α and IL-6 mRNA levels in diabetic adipose tissue without influencing adiponection expression. Moreover, in mesenteric arteries, dendritic cell depletion improved the ability of PVAT to augment acetylcholine-induced vasorelaxation and anti-contractile activity.
In a murine model of T2DM, dendritic cells accumulated predominantly in PVAT, as opposed to the vessel wall, per se. Accumulation of dendritic cells in PVAT was associated with overproduction of pro-inflammatory cytokines, which contributed to an impaired ability of PVAT to augment vasorelaxation and exert anti-contractile activity in T2DM.
人们提出，血管周围脂肪组织（PVAT）中多种免疫细胞亚型的积累会导致 2 型糖尿病（T2DM）中的血管炎症和功能障碍。本研究旨在研究树突状细胞在 PVAT 中的特定作用，以了解其在 T2DM 中血管炎症的发展和 PVAT 介导的血管舒张功能障碍中的作用。
本研究使用 db/db 小鼠（T2DM 模型）及其 Db 杂合子（DbHET）、瘦型和血糖正常对照进行研究。通过将 DbHet 与 Flt3l（缺失 FMS-kinase 酪氨酸激酶的配体）小鼠杂交，进行树突状细胞耗竭。通过 PCR 发现，大多数树突状细胞（CD11c）位于 PVAT 中，而不是血管壁中。流式细胞术同样显示，db/db 小鼠脂肪组织中的树突状细胞积累量多于 DbHET 对照组。与 DbHET 小鼠相比，db/db 小鼠脂肪组织中促炎细胞因子 TNF-α 和 IL-6 的 mRNA 水平升高，抗炎介质脂联素的 mRNA 水平降低。在 db/db 小鼠中（通过流式细胞术证实）耗竭树突状细胞可降低糖尿病脂肪组织中 TNF-α 和 IL-6 的 mRNA 水平，而不影响脂联素的表达。此外，在肠系膜动脉中，耗竭树突状细胞可改善 PVAT 增强乙酰胆碱诱导的血管舒张和抗收缩活性的能力。
在 T2DM 的小鼠模型中，树突状细胞主要积聚在 PVAT 中，而不是血管壁本身。PVAT 中树突状细胞的积累与促炎细胞因子的过度产生有关，这导致了 T2DM 中 PVAT 增强血管舒张和发挥抗收缩活性的能力受损。
