Journal
GEROSCIENCE
Volume 42, Issue 2, Pages 547-561Publisher
SPRINGER
DOI: 10.1007/s11357-020-00179-z
Keywords
Hyperglycemia; ATP depletion; Mitochondria dynamics; Myogenic response; Cerebral vascular smooth muscle cells
Categories
Funding
- NHLBI NIH HHS [R01 HL138685] Funding Source: Medline
- NIA NIH HHS [R01 AG057842, R21 AG050049] Funding Source: Medline
- NIDDK NIH HHS [R01 DK104184] Funding Source: Medline
- NIGMS NIH HHS [P20 GM121334, P20 GM104357] Funding Source: Medline
- NIH HHS [DK104184, HL138685] Funding Source: Medline
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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.
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