Abstract
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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References
Ahn B, et al. Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass. Redox Biol. 2018;17:47–58. https://doi.org/10.1016/j.redox.2018.04.004.
American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37(Suppl 1):S81–90. https://doi.org/10.2337/dc14-S081.
Assar ME, Angulo J, Rodriguez-Manas L. Diabetes and ageing-induced vascular inflammation. J Physiol. 2016;594:2125–46. https://doi.org/10.1113/JP270841.
Braun DJ, Bachstetter AD, Sudduth TL, Wilcock DM, Watterson DM, Van Eldik LJ. Genetic knockout of myosin light chain kinase (MLCK210) prevents cerebral microhemorrhages and attenuates neuroinflammation in a mouse model of vascular cognitive impairment and dementia. Geroscience. 2019;41:671–9. https://doi.org/10.1007/s11357-019-00072-4.
Butler TM, Siegman MJ. High-energy phosphate metabolism in vascular smooth muscle. Annu Rev Physiol. 1985;47:629–43. https://doi.org/10.1146/annurev.ph.47.030185.003213.
Chalmers S, McCarron JG. The mitochondrial membrane potential and Ca<sup>2+</sup> oscillations in smooth muscle. J Cell Sci. 2008;121:75. https://doi.org/10.1242/jcs.014522.
Chao CT, Wang J, Wu HY, Huang JW, Chien KL. Age modifies the risk factor profiles for acute kidney injury among recently diagnosed type 2 diabetic patients: a population-based study. Geroscience. 2018;40:201–17. https://doi.org/10.1007/s11357-018-0013-3.
Cipolla MJ, Gokina NI, Osol G. Pressure-induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior. FASEB J. 2002;16:72–6. https://doi.org/10.1096/cj.01-0104hyp.
Corriere M, Rooparinesingh N, Kalyani RR. Epidemiology of diabetes and diabetes complications in the elderly: an emerging public health burden. Curr Diab Rep. 2013;13:805–13. https://doi.org/10.1007/s11892-013-0425-5.
Cory AH, Owen TC, Barltrop JA, Cory JG. Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun. 1991;3:207–12. https://doi.org/10.3727/095535491820873191.
Csiszar A, et al. Role of endothelial NAD(+) deficiency in age-related vascular dysfunction. Am J Physiol Heart Circ Physiol. 2019;316:H1253–66. https://doi.org/10.1152/ajpheart.00039.2019.
Ergul A, Kelly-Cobbs A, Abdalla M, Fagan SC. Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets. 2012;12:148–58.
Fan F, et al. 20-Hydroxyeicosatetraenoic acid contributes to the inhibition of K+ channel activity and vasoconstrictor response to angiotensin II in rat renal microvessels. PloS One. 2013;8:e82482. https://doi.org/10.1371/journal.pone.0082482.
Fan F, Geurts AM, Pabbidi MR, Smith SV, Harder DR, Jacob H, et al. Zinc-finger nuclease knockout of dual-specificity protein phosphatase-5 enhances the myogenic response and autoregulation of cerebral blood flow in FHH.1BN rats. PLoS One. 2014;9:e112878. https://doi.org/10.1371/journal.pone.0112878.
Fan F, Geurts AM, Murphy SR, Pabbidi MR, Jacob HJ, Roman RJ. Impaired myogenic response and autoregulation of cerebral blood flow is rescued in CYP4A1 transgenic Dahl salt-sensitive rat. Am J Physiol Regul Integr Comp Physiol. 2015;308:R379–90. https://doi.org/10.1152/ajpregu.00256.2014.
Fan F, Pabbidi MR, Ge Y, Li L, Wang S, Mims PN, et al. Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries. Am J Physiol Renal Physiol. 2017;312:F971–81. https://doi.org/10.1152/ajprenal.00529.2016.
Fulop GA, et al. Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. Geroscience. 2018;40:513–21. https://doi.org/10.1007/s11357-018-0047-6.
Gilkerson RW, Margineantu DH, Capaldi RA, Selker JML. Mitochondrial DNA depletion causes morphological changes in the mitochondrial reticulum of cultured human cells. FEBS Lett. 2000;474:1–4.
Goldberg IJ, Dansky HM. Diabetic vascular disease: an experimental objective. Arterioscler Thromb Vasc Biol. 2006;26:1693–701. https://doi.org/10.1161/01.ATV.0000231521.76545.f6.
Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011;13:589–98. https://doi.org/10.1038/ncb2220.
Hill MA, Meininger GA. Impaired arteriolar myogenic reactivity in early experimental diabetes. Diabetes. 1993;42:1226–32. https://doi.org/10.2337/diab.42.9.1226.
Hoyer S, Oesterreich K, Wagner O. Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J Neurol. 1988;235:143–8. https://doi.org/10.1007/bf00314304.
Jendrach M, Mai S, Pohl S, Voth M, Bereiter-Hahn J. Short- and long-term alterations of mitochondrial morphology, dynamics and mtDNA after transient oxidative stress. Mitochondrion. 2008;8:293–304. https://doi.org/10.1016/j.mito.2008.06.001.
Jose C, Bellance N, Rossignol R. Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma? Biochim Biophys Acta. 2011;1807:552–61. https://doi.org/10.1016/j.bbabio.2010.10.012.
Karbowski M, Youle RJ. Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ. 2003;10:870–80.
Kargl CK, Nie Y, Evans S, Stout J, Shannahan JH, Kuang S, et al. Factors secreted from high glucose treated endothelial cells impair expansion and differentiation of human skeletal muscle satellite cells. J Physiol. 2019;597:5109–24. https://doi.org/10.1113/JP278165.
Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51:2944–50. https://doi.org/10.2337/diabetes.51.10.2944.
Kelly-Cobbs A, Elgebaly MM, Li W, Ergul A. Pressure-independent cerebrovascular remodelling and changes in myogenic reactivity in diabetic Goto-Kakizaki rat in response to glycaemic control. Acta Physiol (Oxf). 2011;203:245–51. https://doi.org/10.1111/j.1748-1716.2010.02230.x.
Kiss T, et al. Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. Geroscience. 2020. https://doi.org/10.1007/s11357-020-00165-5.
Kojima N, Williams JM, Takahashi T, Miyata N, Roman RJ. Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J Pharmacol Exp Ther. 2013;345:464–72.
Lagaud GJ, Masih-Khan E, Kai S, van Breemen C, Dube GP. Influence of type II diabetes on arterial tone and endothelial function in murine mesenteric resistance arteries. J Vasc Res. 2001;38:578–89.
Lee H, et al. Increased mitochondrial activity in renal proximal tubule cells from young spontaneously hypertensive rats. Kidney Int. 2014;85:561–9. https://doi.org/10.1038/ki.2013.397.
Legros F, Lombes A, Frachon P, Rojo M. Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell. 2002;13:4343–54. https://doi.org/10.1091/mbc.e02-06-0330.
Lemasters JJ. Variants of mitochondrial autophagy: types 1 and 2 mitophagy and micromitophagy (type 3). Redox Biol. 2014;2:749–54. https://doi.org/10.1016/j.redox.2014.06.004.
Lieven CJ, Vrabec JP, Levin LA. The effects of oxidative stress on mitochondrial transmembrane potential in retinal ganglion cells. Antioxid Redox Signal. 2003;5:641–6. https://doi.org/10.1089/152308603770310310.
McCarron JG, Wilson C, Sandison ME, Olson ML, Girkin JM, Saunter C, et al. From structure to function: mitochondrial morphology, motion and shaping in vascular smooth muscle. J Vasc Res. 2013;50:357–71. https://doi.org/10.1159/000353883.
McDaniel CF. Diabetes: a model of oxidative accelerated aging. Age (Omaha). 1999;22:145–8. https://doi.org/10.1007/s11357-999-0016-1.
Muroya Y, He X, Fan L, Wang S, Xu R, Fan F, et al. Enhanced renal ischemia-reperfusion injury in aging and diabetes. Am J Physiol Renal Physiol. 2018;315:F1843–54. https://doi.org/10.1152/ajprenal.00184.2018.
Nobrega MA, Fleming S, Roman RJ, Shiozawa M, Schlick N, Lazar J, et al. Initial characterization of a rat model of diabetic nephropathy. Diabetes. 2004;53:735–42.
Ohlmann P, et al. Deletion of MLCK210 induces subtle changes in vascular reactivity but does not affect cardiac function. Am J Physiol Heart Circ Physiol. 2005;289:H2342–9. https://doi.org/10.1152/ajpheart.00511.2004.
Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, et al. Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol. 2010;191:1141. https://doi.org/10.1083/jcb.201007152.
Paul RJ. Functional compartmentalization of oxidative and glycolytic metabolism in vascular smooth muscle. Am J Physiol. 1983;244:C399–409. https://doi.org/10.1152/ajpcell.1983.244.5.C399.
Pehar M, Harlan BA, Killoy KM, Vargas MR. Nicotinamide adenine dinucleotide metabolism and neurodegeneration. Antioxid Redox Signal. 2018;28:1652–68. https://doi.org/10.1089/ars.2017.7145.
Phong B, Avery L, Menk AV, Delgoffe GM, Kane LP. Cutting edge: murine mast cells rapidly modulate metabolic pathways essential for distinct effector functions. J Immunol. 2017;198:640–4. https://doi.org/10.4049/jimmunol.1601150.
Robinson KM, Janes MS, Beckman JS. The selective detection of mitochondrial superoxide by live cell imaging. Nat Protoc. 2008;3:941–7. https://doi.org/10.1038/nprot.2008.56.
Samaras K, et al. The impact of glucose disorders on cognition and brain volumes in the elderly: the Sydney Memory and Ageing Study. Age (Dordr). 2014;36:977–93. https://doi.org/10.1007/s11357-013-9613-0.
Shekhar S, et al. Impaired cerebral autoregulation-a common neurovascular pathway in diabetes may play a critical role in diabetes-related Alzheimer’s disease. Curr Res Diabetes Obes J. 2017;2:555587.
Shen Q, et al. Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Mol Biol Cell. 2014;25:145–59. https://doi.org/10.1091/mbc.E13-09-0525.
Shenouda SM, et al. Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation. 2011;124:444–53. https://doi.org/10.1161/CIRCULATIONAHA.110.014506.
Song Z, Chen H, Fiket M, Alexander C, Chan DC. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007;178:749. https://doi.org/10.1083/jcb.200704110.
Springo Z, Tarantini S, Toth P, Tucsek Z, Koller A, Sonntag WE, et al. Aging exacerbates pressure-induced mitochondrial oxidative stress in mouse cerebral arteries. J Gerontol A Biol Sci Med Sci. 2015a;70:1355–9. https://doi.org/10.1093/gerona/glu244.
Springo Z, Toth P, Tarantini S, Ashpole NM, Tucsek Z, Sonntag WE, et al. Aging impairs myogenic adaptation to pulsatile pressure in mouse cerebral arteries. J Cereb Blood Flow Metab. 2015b;35:527–30. https://doi.org/10.1038/jcbfm.2014.256.
Sure VN, et al. A novel high-throughput assay for respiration in isolated brain microvessels reveals impaired mitochondrial function in the aged mice. Geroscience. 2018;40:365–75. https://doi.org/10.1007/s11357-018-0037-8.
Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endocr Metab Disord. 2010;11:61–74. https://doi.org/10.1007/s11154-010-9134-4.
Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, et al. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 2019a;24:101192. https://doi.org/10.1016/j.redox.2019.101192.
Tarantini S, et al. Treatment with the poly(ADP-ribose) polymerase inhibitor PJ-34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging. Geroscience. 2019b;41:533–42. https://doi.org/10.1007/s11357-019-00101-2.
Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62:341–60. https://doi.org/10.1042/EBC20170104.
Toth P, et al. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab. 2013;33:1732–42. https://doi.org/10.1038/jcbfm.2013.143.
van der Bliek AM, Shen Q, Kawajiri S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb Perspect Biol. 2013;5. https://doi.org/10.1101/cshperspect.a011072.
Walmsley D, Wiles PG. Myogenic microvascular responses are impaired in long-duration type 1 diabetes. Diabet Med. 1990;7:222–7.
Wang Q, et al. Mitochondrial dysfunction and apoptosis in cumulus cells of type I diabetic mice. PLoS One. 2010;5:e15901. https://doi.org/10.1371/journal.pone.0015901.
Wang S, Mims PN, Roman RJ, Fan F. Is beta-amyloid accumulation a cause or consequence of Alzheimer’s disease? J Alzheimers Parkinsonism Dement. 2016;1:007.
Weil BR, Abarbanell AM, Herrmann JL, Wang Y, Meldrum DR. High glucose concentration in cell culture medium does not acutely affect human mesenchymal stem cell growth factor production or proliferation. Am J Physiol Regul Integr Comp Physiol. 2009;296:R1735–43. https://doi.org/10.1152/ajpregu.90876.2008.
Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010;11:872–84. https://doi.org/10.1038/nrm3013.
Yoon Y, Galloway CA, Jhun BS, Yu T. Mitochondrial dynamics in diabetes. Antioxid Redox Signal. 2011;14:439–57. https://doi.org/10.1089/ars.2010.3286.
Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337:1062–5. https://doi.org/10.1126/science.1219855.
Zhang B, et al. SIRT3 overexpression antagonizes high glucose accelerated cellular senescence in human diploid fibroblasts via the SIRT3-FOXO1 signaling pathway. Age (Dordr). 2013;35:2237–53. https://doi.org/10.1007/s11357-013-9520-4.
Zhou H, Zhang X, Lu J. Progress on diabetic cerebrovascular diseases. Bosn J Basic Med Sci. 2014;14:185–90. https://doi.org/10.17305/bjbms.2014.4.203.
Zorova LD, et al. Mitochondrial membrane potential. Anal Biochem. 2018;552:50–9. https://doi.org/10.1016/j.ab.2017.07.009.
Funding
This work was supported by the National Institutes of Health (AG050049, AG057842, P20GM104357, DK104184, and HL138685) and the American Heart Association (16GRNT31200036 and 20PRE35210043).
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Guo, Y., Wang, S., Liu, Y. et al. Accelerated cerebral vascular injury in diabetes is associated with vascular smooth muscle cell dysfunction. GeroScience 42, 547–561 (2020). https://doi.org/10.1007/s11357-020-00179-z
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DOI: https://doi.org/10.1007/s11357-020-00179-z