Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Life Sci. 2023 Mar 1;316:121416. doi: 10.1016/j.lfs.2023.121416. Epub 2023 Jan 21.
Blood vessels are surrounded by perivascular adipose tissue (PVAT), which plays an important role in vascular tonus regulation due to its anticontractile effect; however, this effect is impaired in obesity. We previously demonstrated that miRNA-22 is involved in obesity-related metabolic disorders. However, the impact of miRNA-22 on vascular reactivity and PVAT function is unknown.
To investigate the role of miRNA-22 on vascular reactivity and its impact on obesity-induced PVAT dysfunction.
Wild-type and miRNA-22 knockout (KO) mice were fed a control or a high-fat (HF) diet. To characterize the vascular response, concentration-responses curves to noradrenaline were performed in PVAT- or PVAT+ thoracic aortic rings in absence and presence of L-NAME. Expression of adipogenic and thermogenic markers and NOS isoforms were evaluated by western blotting or qPCR.
HF diet and miRNA-22 deletion reduced noradrenaline-induced contraction in PVAT- aortic rings. Additionally, miRNA-22 deletion increased noradrenaline-induced contraction in PVAT+ aortic rings without affecting its sensitivity; however, this effect was not observed in miRNA-22 KO mice fed a HF diet. Interestingly, miRNA-22 deletion reduced the contraction of aortic rings to noradrenaline via a NOS-dependent mechanism. Moreover, HF diet abolished the NOS-mediated anticontractile effect of PVAT, which was attenuated by miRNA-22 deletion. Mechanistically, we found that PVAT from miRNA-22 KO mice fed a HF diet presented increased protein expression of nNOS.
These results suggest that miRNA-22 is important for aorta reactivity under physiological circumstances and its deletion attenuates the loss of the NOS-mediated anticontractile effect of PVAT in obesity.
血管周围有血管周脂肪组织 (PVAT)，由于其抗收缩作用，在血管张力调节中起重要作用；然而，这种作用在肥胖中受损。我们之前证明 miRNA-22 参与肥胖相关的代谢紊乱。然而，miRNA-22 对血管反应性及其对肥胖诱导的 PVAT 功能障碍的影响尚不清楚。
研究 miRNA-22 在血管反应性中的作用及其对肥胖诱导的 PVAT 功能障碍的影响。
给予野生型和 miRNA-22 敲除 (KO) 小鼠对照或高脂肪 (HF) 饮食。为了描述血管反应，在不存在和存在 L-NAME 的情况下，在 PVAT 或 PVAT+胸主动脉环中进行去甲肾上腺素浓度反应曲线。通过 Western 印迹或 qPCR 评估脂肪生成和生热标记物和 NOS 同工型的表达。
HF 饮食和 miRNA-22 缺失降低了 PVAT-主动脉环中去甲肾上腺素诱导的收缩。此外，miRNA-22 缺失增加了 PVAT+主动脉环中去甲肾上腺素诱导的收缩，但不影响其敏感性；然而，在 HF 饮食喂养的 miRNA-22 KO 小鼠中未观察到这种作用。有趣的是，miRNA-22 缺失通过依赖 NOS 的机制降低了去甲肾上腺素对主动脉环的收缩作用。此外，HF 饮食消除了 PVAT 的 NOS 介导的抗收缩作用，而 miRNA-22 缺失减弱了这种作用。从机制上讲，我们发现 HF 饮食喂养的 miRNA-22 KO 小鼠的 PVAT 中 nNOS 的蛋白表达增加。
这些结果表明，miRNA-22 在生理情况下对主动脉反应性很重要，其缺失减弱了肥胖中 PVAT 的 NOS 介导的抗收缩作用的丧失。
