Obesity-related cardiovascular risk, end points, and mortality are strongly related to arterial stiffening. Current therapeutic approaches for arterial stiffening are not focused on direct targeting within the vessel. Perivascular adipose tissue (PVAT) surrounding the artery has been shown to modulate vascular function and inflammation. Peroxisome proliferator-activated receptor γ (PPARγ) activation significantly decreases arterial stiffness and inflammation in diabetic patients with coronary artery disease. Thus, we hypothesized that PPARγ activation alters the PVAT microenvironment, thereby creating a favorable environment for the attenuation of arterial stiffening in obesity. Obese ob/ob mice were used to investigate the effect of PPARγ activation on the attenuation of arterial stiffening. Various cell types, including macrophages, fibroblasts, adipocytes, and vascular smooth muscle cells, were used to test the inhibitory effect of pioglitazone, a PPARγ agonist, on the expression of elastolytic enzymes. PPARγ activation by pioglitazone effectively attenuated arterial stiffening in ob/ob mice. This beneficial effect was not associated with the repartitioning of fat from or changes in the browning of the PVAT depot but was strongly related to improvement of the PVAT microenvironment, as evidenced by reduction in the expression of pro-inflammatory and pro-oxidative factors. Pioglitazone treatment attenuated obesity-induced elastin fiber fragmentation and elastolytic activity and ameliorated the obesity-induced upregulation of cathepsin S and metalloproteinase 12, predominantly in the PVAT. In vitro, pioglitazone downregulated Ctss and Mmp12 in macrophages, fibroblasts, and adipocytes—cell types residing within the adventitia and PVAT. Ultimately, several PPARγ binding sites were found in Ctss and Mmp12 in Raw 264.7 and 3T3-L1 cells, suggesting a direct regulatory mechanism by which PPARγ activation repressed the expression of Ctss and Mmp-12 in macrophages and fibroblasts. PPARγ activation attenuated obesity-induced arterial stiffening and reduced the inflammatory and oxidative status of PVAT. The improvement of the PVAT microenvironment further contributed to the amelioration of elastin fiber fragmentation, elastolytic activity, and upregulated expression of Ctss and Mmp12. Our data highlight the PVAT microenvironment as an important target against arterial stiffening in obesity and provide a novel strategy for the potential clinical use of PPARγ agonists as a therapeutic against arterial stiffness through modulation of PVAT function.

中文翻译：

---

PPARγ激活改善血管周围脂肪组织的微环境并减轻肥胖患者的主动脉硬化

肥胖相关的心血管风险、终点和死亡率与动脉硬化密切相关。当前的动脉硬化治疗方法并不集中在血管内的直接靶向。动脉周围的血管周围脂肪组织 (PVAT) 已被证明可以调节血管功能和炎症。过氧化物酶体增殖物激活受体 γ (PPARγ) 激活显着降低患有冠状动脉疾病的糖尿病患者的动脉僵硬度和炎症。因此，我们假设 PPARγ 激活会改变 PVAT 微环境，从而为肥胖中动脉硬化的衰减创造有利的环境。肥胖的 ob/ob 小鼠被用来研究 PPARγ 激活对动脉硬化减弱的影响。各种细胞类型，包括巨噬细胞、成纤维细胞、脂肪细胞和血管平滑肌细胞用于测试吡格列酮（一种 PPARγ 激动剂）对弹性分解酶表达的抑制作用。吡格列酮激活 PPARγ 可有效减轻 ob/ob 小鼠的动脉硬化。这种有益效果与 PVAT 库中脂肪的重新分配或褐变的变化无关，但与 PVAT 微环境的改善密切相关，如促炎和促氧化因子表达的减少所证明的那样。吡格列酮治疗减弱了肥胖诱导的弹性蛋白纤维断裂和弹性分解活性，并改善了肥胖诱导的组织蛋白酶 S 和金属蛋白酶 12 的上调，主要是在 PVAT 中。在体外，吡格列酮下调巨噬细胞、成纤维细胞、和脂肪细胞——存在于外膜和 PVAT 中的细胞类型。最终，在 Raw 264.7 和 3T3-L1 细胞的 Ctss 和 Mmp12 中发现了几个 PPARγ 结合位点，表明 PPARγ 激活抑制巨噬细胞和成纤维细胞中 Ctss 和 Mmp-12 表达的直接调节机制。PPARγ 激活减弱了肥胖引起的动脉硬化，并降低了 PVAT 的炎症和氧化状态。PVAT 微环境的改善进一步有助于改善弹性蛋白纤维断裂、弹性分解活性以及 Ctss 和 Mmp12 的上调表达。