Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.
Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, China.
Geroscience. 2020 Apr;42(2):547-561. doi: 10.1007/s11357-020-00179-z. Epub 2020 Mar 12.
Individuals with diabetes are more susceptible to cerebral vascular aging. However, the underlying mechanisms are not well elucidated. The present study examined whether the myogenic response of the middle cerebral artery (MCA) is impaired in diabetic rats due to high glucose (HG)-induced cerebral vascular smooth muscle cell (CVSMC) dysfunction, and whether this is associated with ATP depletion and changes in mitochondrial dynamics and membrane potential. The diameters of the MCA of diabetic rats increased to 135.3 ± 11.3% when perfusion pressure was increased from 40 to 180 mmHg, while it fell to 85.1 ± 3.1% in non-diabetic controls. The production of ROS and mitochondrial-derived superoxide were enhanced in cerebral arteries of diabetic rats. Levels of mitochondrial superoxide were significantly elevated in HG-treated primary CVSMCs, which was associated with decreased ATP production, mitochondrial respiration, and membrane potential. The expression of OPA1 was reduced, and MFF was elevated in HG-treated CVSMCs in association with fragmented mitochondria. Moreover, HG-treated CVSMCs displayed lower contractile and proliferation capabilities. These results demonstrate that imbalanced mitochondrial dynamics (increased fission and decreased fusion) and membrane depolarization contribute to ATP depletion in HG-treated CVSMCs, which promotes CVSMC dysfunction and may play an essential role in exacerbating the impaired myogenic response in the cerebral circulation in diabetes and accelerating vascular aging.
糖尿病个体更容易发生脑血管老化。然而，其潜在机制尚不清楚。本研究探讨了高血糖（HG）是否会导致脑血管平滑肌细胞（CVSMC）功能障碍，从而损害糖尿病大鼠大脑中动脉（MCA）的肌源性反应，以及这是否与三磷酸腺苷（ATP）耗竭以及线粒体动力学和膜电位变化有关。当灌注压从 40mmHg 增加到 180mmHg 时，糖尿病大鼠 MCA 的直径增加到 135.3±11.3%，而非糖尿病对照组则下降到 85.1±3.1%。糖尿病大鼠脑血管内 ROS 和线粒体来源的超氧阴离子生成增加。HG 处理的原代 CVSMC 中线粒体超氧阴离子水平显著升高，与 ATP 生成减少、线粒体呼吸和膜电位降低有关。OPA1 的表达减少，MFF 升高，与片段化的线粒体有关。此外，HG 处理的 CVSMC 表现出较低的收缩和增殖能力。这些结果表明，失衡的线粒体动力学（增加的分裂和减少的融合）和膜去极化导致 HG 处理的 CVSMC 中 ATP 耗竭，从而促进 CVSMC 功能障碍，并可能在加剧糖尿病患者脑血管循环中受损的肌源性反应和加速血管老化方面发挥重要作用。
