Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Chongqing Institute of Hypertension, Daping Hospital, Third Military Medical University, Chongqing, PR China.
Hypertens Res. 2010 May;33(5):446-53. doi: 10.1038/hr.2010.11. Epub 2010 Feb 26.
Perivascular adipose tissue (PVAT) is implicated in the regulation of vascular function in the physiological state, but the modulatory effect of PVAT on vasculature during obesity is poorly understood. Endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) participate in the regulation of vascular function. We therefore investigated whether PVAT has a potential role through the AMPK/mTOR pathway in obesity-related vascular dysfunction. Wistar rats on a high-fat diet (HFD) for 6 months had higher periaortic fat mass compared with rats on a chow diet (3.31+/-0.56 vs. 2.34+/-0.28 g, P<0.05). Obesity-related impairment of endothelium-dependent relaxation of the aorta was markedly attenuated by temporary periaortic fat removal whereas obesity-related enhancement of contractile performance was unaffected. Rats on an HFD had thicker aortic tunica medias (180.06+/-7.56 vs. 128.14+/-13.21 microm for rats on a chow diet, P<0.01) and larger periaortic adipocytes than rats on a chow diet (1209.00+/-62.65 vs. 447.20+/-21.31 microm(2), respectively, P<0.01). Furthermore, mesenteric arterial rings incubated with periaortic fat from rats on an HFD demonstrated lower endothelium-dependent relaxation. This effect was absent in mesenteric arterial rings incubated with periaortic fat from rats on a chow diet. Moreover, an HFD led to a downregulation of AMPK and eNOS in the aorta with a concurrent upregulation of mTOR. In a parallel in vitro study, culturing vascular smooth muscle cells with periaortic adipocytes from rats on an HFD reduced the AMPK phosphorylation and increased mTOR phosphorylation, and the latter one was blocked by the incubation of compound C. We conclude that PVAT likely impacts obesity-related vascular dysfunction and remodeling through impairment of eNOS-mediated vasodilatation and the AMPK/mTOR pathway.
血管周围脂肪组织（PVAT）参与调节生理状态下的血管功能，但肥胖时 PVAT 对血管的调节作用知之甚少。内皮型一氧化氮合酶（eNOS）、AMP 激活的蛋白激酶（AMPK）和哺乳动物雷帕霉素靶蛋白（mTOR）参与血管功能的调节。因此，我们研究了肥胖相关血管功能障碍中，PVAT 是否通过 AMPK/mTOR 途径发挥作用。高脂饮食（HFD）喂养 6 个月的 Wistar 大鼠的主动脉旁脂肪量明显高于正常饮食（chow）大鼠（3.31+/-0.56 比 2.34+/-0.28 g，P<0.05）。暂时去除主动脉旁脂肪可明显减轻肥胖引起的血管舒张功能障碍，而肥胖引起的收缩功能增强则不受影响。HFD 大鼠的主动脉中层厚度（180.06+/-7.56 比 chow 大鼠的 128.14+/-13.21 µm，P<0.01）和主动脉旁脂肪细胞体积（1209.00+/-62.65 比 chow 大鼠的 447.20+/-21.31 µm2，P<0.01）均大于 chow 大鼠。此外，用 HFD 大鼠的主动脉旁脂肪孵育的肠系膜动脉环显示出较低的内皮依赖性舒张。用 chow 大鼠的主动脉旁脂肪孵育的肠系膜动脉环则没有这种作用。此外，HFD 导致主动脉 AMPK 和 eNOS 下调，同时 mTOR 上调。在一项平行的体外研究中，用 HFD 大鼠的主动脉旁脂肪细胞培养血管平滑肌细胞，导致 AMPK 磷酸化减少，mTOR 磷酸化增加，后者可被化合物 C 阻断。我们的结论是，PVAT 可能通过损害 eNOS 介导的血管舒张和 AMPK/mTOR 途径，影响肥胖相关的血管功能障碍和重塑。
