From the Key Laboratory for Arteriosclerology of Hunan Province, Institute of Cardiovascular Disease, University of South China, Hengyang (W.X., Z.J.).
Department of Internal Medicine, Frankel Cardiovascular Center (W.X., X.Z., L.V., O.R., M.T.G.-B., Y.G., Y.F., T.Z., J.Z., L.C.).
Arterioscler Thromb Vasc Biol. 2018 Aug;38(8):1738-1747. doi: 10.1161/ATVBAHA.118.311367.
Objective- Perivascular adipose tissue (PVAT) contributes to vascular homeostasis by producing paracrine factors. Previously, we reported that selective deletion of PPARγ (peroxisome proliferator-activated receptor γ) in vascular smooth muscle cells resulted in concurrent loss of PVAT and enhanced atherosclerosis in mice. To address the causal relationship between loss of PVAT and atherosclerosis, we used BA-PPARγ-KO (brown adipocyte-specific PPARγ knockout) mice. Approach and Results- Deletion of PPARγ in brown adipocytes did not affect PPARγ in white adipocytes or vascular smooth muscle cells or PPARα and PPARδ expression in brown adipocytes. However, development of PVAT and interscapular brown adipose tissue was remarkably impaired, associated with reduced expression of genes encoding lipogenic enzymes in the BA-PPARγ-KO mice. Thermogenesis in brown adipose tissue was significantly impaired with reduced expression of thermogenesis genes in brown adipose tissue and compensatory increase in subcutaneous and gonadal white adipose tissues. Remarkably, basal expression of inflammatory genes and macrophage infiltration in PVAT and brown adipose tissue were significantly increased in the BA-PPARγ-KO mice. BA-PPARγ-KO mice were crossbred with ApoE KO (apolipoprotein E knockout) mice to investigate the development of atherosclerosis. Flow cytometry analysis confirmed increased systemic and PVAT inflammation. Consequently, atherosclerotic lesions were significantly increased in mice with impaired PVAT development, thus indicating that the lack of normal PVAT is sufficient to drive increased atherosclerosis. Conclusions- PPARγ is required for functional PVAT development. PPARγ deficiency in PVAT, while still expressed in vascular smooth muscle cell, enhances atherosclerosis and results in vascular and systemic inflammation, providing new insights on the specific roles of PVAT in atherosclerosis and cardiovascular disease at large.
目的-血管周围脂肪组织（PVAT）通过产生旁分泌因子来促进血管稳态。先前，我们报道过血管平滑肌细胞中过氧化物酶体增殖物激活受体γ（PPARγ）的选择性缺失会导致 PVAT 同时丢失，并增强小鼠的动脉粥样硬化。为了解决 PVAT 丢失与动脉粥样硬化之间的因果关系，我们使用了 BA-PPARγ-KO（棕色脂肪细胞特异性 PPARγ 敲除）小鼠。
方法和结果-棕色脂肪细胞中 PPARγ 的缺失不影响白色脂肪细胞或血管平滑肌细胞中的 PPARγ，也不影响棕色脂肪细胞中 PPARα 和 PPARδ 的表达。然而，棕色脂肪细胞中 PVAT 和肩胛间棕色脂肪组织的发育显著受损，与 BA-PPARγ-KO 小鼠中编码脂肪生成酶的基因表达减少有关。棕色脂肪组织的产热显著受损，棕色脂肪组织中产热基因的表达减少，而皮下和性腺白色脂肪组织的代偿性增加。值得注意的是，BA-PPARγ-KO 小鼠的 PVAT 和棕色脂肪组织中炎症基因的基础表达和巨噬细胞浸润显著增加。
BA-PPARγ-KO 小鼠与 ApoE KO（载脂蛋白 E 敲除）小鼠杂交，以研究动脉粥样硬化的发展。流式细胞术分析证实了全身和 PVAT 炎症的增加。因此，在 PVAT 发育受损的小鼠中，动脉粥样硬化病变显著增加，这表明正常 PVAT 的缺失足以导致动脉粥样硬化的增加。
结论-PPARγ 是功能性 PVAT 发育所必需的。PVAT 中的 PPARγ 缺失，而在血管平滑肌细胞中仍有表达，会增强动脉粥样硬化并导致血管和全身炎症，这为 PVAT 在动脉粥样硬化和心血管疾病中的特定作用提供了新的见解。
