Abstract
In cerebral arteries, alterations of vascular reactivity have been observed but not well molecularly characterized. Therefore, we have hypothesized that cerebrovascular reactivity could be modified by aging via a modification of Ca2+ signaling in smooth muscle cells. Ca2+ signals and gene expression implicated in contraction have been measured in posterior and middle cerebral arteries from young (2–3 months) and old (20–22 months) C57Bl6/J mice. Aging induced a decrease of KCl- and caffeine-induced contraction as well as a decrease of the amplitudes and an increase of the durations of KCl- and caffeine-induced Ca2+ signals. These results could be linked with the decrease of gene expression coding for Cav1.2, RyR2, SERCA2, PLB, STIM1, TRIC-B, and the increase of FKBP12.6 and TPCN1 gene expression. Finally, aging induced a modification of InsP3 subtype expression pattern responsible for a modification of the InsP3 affinity to activate Ca2+ signals. These results show that aging induces a decrease of contractility correlated with modifications of the expression of genes encoding Ca2+ signaling toolkit. Globally, the amplitude of Ca2+ signals was decreased, whereas their duration was increased by a defection of Ca2+ store refilling.
Similar content being viewed by others
References
Belin de Chantemele EJ, Retailleau K, Pinaud F, Vessieres E, Bocquet A, Guihot AL, Lemaire B, Domenga V, Baufreton C, Loufrani L, Joutel A, Henrion D (2008) Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries. Arterioscler Thromb Vasc Biol 28(12):2216–2224. doi:10.1161/ATVBAHA.108.171751
Berridge MJ (2003) Cardiac calcium signalling. Biochem Soc Trans 31(Pt 5):930–933. doi:10.1042/
Berridge MJ (2008) Smooth muscle cell calcium activation mechanisms. J Physiol 586(Pt 21):5047–5061. doi:10.1113/jphysiol.2008.160440
Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1(1):11–21. doi:10.1038/35036035
Blood AB, Zhao Y, Long W, Zhang L, Longo LD (2002) L-type Ca2+ channels in fetal and adult ovine cerebral arteries. Am J Physiol Regul Integr Comp Physiol 282(1):R131–R138. doi:10.1152/ajpregu.00318.2001
Boittin FX, Galione A, Evans AM (2002) Nicotinic acid adenine dinucleotide phosphate mediates Ca2+ signals and contraction in arterial smooth muscle via a two-pool mechanism. Circ Res 91(12):1168–1175
Brailoiu E, Churamani D, Cai X, Schrlau MG, Brailoiu GC, Gao X, Hooper R, Boulware MJ, Dun NJ, Marchant JS, Patel S (2009) Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling. J Cell Biol 186(2):201–209. doi:10.1083/jcb.200904073
Brini M, Bano D, Manni S, Rizzuto R, Carafoli E (2000) Effects of PMCA and SERCA pump overexpression on the kinetics of cell Ca2+ signalling. EMBO J 19(18):4926–4935
Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang K-T, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, Zhu MX (2009) NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature 459 (7246):596-600. doi:http://www.nature.com/nature/journal/v459/n7246/suppinfo/nature08030_S1.html
Camandola S, Mattson MP (2011) Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease. Biochim Biophys Acta (BBA) - Mol Cell Res 1813(5):965–973. doi:10.1016/j.bbamcr.2010.10.005
Coussin F, Macrez N, Morel J-L, Mironneau J (2000) Requirement of ryanodine receptor subtypes 1 and 2 for Ca2+ -induced Ca2+ release in vascular myocytes. J Biol Chem 275(13):9596–9603. doi:10.1074/jbc.275.13.9596
Dabertrand F, Fritz N, Mironneau J, Macrez N, Morel JL (2007) Role of RYR3 splice variants in calcium signaling in mouse nonpregnant and pregnant myometrium. Am J Physiol Cell Physiol 293(3):C848–C854. doi:10.1152/ajpcell.00069.2007
Dabertrand F, Mironneau J, Macrez N, Morel JL (2008) Full length ryanodine receptor subtype 3 encodes spontaneous calcium oscillations in native duodenal smooth muscle cells. Cell Calcium 44(2):180–189. doi:10.1016/j.ceca.2007.11.009
Dabertrand F, Porte Y, Macrez N, Morel J-L (2012) Spaceflight regulates ryanodine receptor subtype 1 in portal vein myocytes in the opposite way of hypertension. J Appl Physiol 112(3):471–480. doi:10.1152/japplphysiol.00733.2011
Davis MJ, Hill MA (1999) Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 79(2):387–423
del Corsso C, Ostrovskaya O, McAllister CE, Murray K, Hatton WJ, Gurney AM, Spencer NJ, Wilson SM (2006) Effects of aging on Ca2+ signaling in murine mesenteric arterial smooth muscle cells. Mech Ageing Dev 127(4):315–323. doi:10.1016/j.mad.2005.12.001
Disterhoft JF, Thompson LT, Moyer JR Jr, Mogul DJ (1996) Calcium-dependent afterhyperpolarization and learning in young and aging hippocampus. Life Sci 59(5–6):413–420
Fellner SK, Arendshorst WJ (2005) Angiotensin II Ca2+ signaling in rat afferent arterioles: stimulation of cyclic ADP ribose and IP3 pathways. Am J Physiol Ren Physiol 288(4):F785–F791. doi:10.1152/ajprenal.00372.2004
Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel S-H, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441 (7090):179-185. doi:http://www.nature.com/nature/journal/v441/n7090/suppinfo/nature04702_S1.html
Fritz N, Macrez N, Mironneau J, Jeyakumar LH, Fleischer S, Morel JL (2005) Ryanodine receptor subtype 2 encodes Ca2+ oscillations activated by acetylcholine via the M2 muscarinic receptor/cADP-ribose signalling pathway in duodenum myocytes. J Cell Sci 118(Pt 10):2261–2270. doi:10.1242/jcs.02344
Fritz N, Mironneau J, Macrez N, Morel JL (2008) Acetylcholine-induced Ca2+ oscillations are modulated by a Ca2+ regulation of InsP3R2 in rat portal vein myocytes. Pflugers Arch Eur J Physiol 456(2):277–283. doi:10.1007/s00424-007-0379-z
Gant JC, Sama MM, Landfield PW, Thibault O (2006) Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+ -Induced Ca2+ release. J Neurosci 26(13):3482–3490. doi:10.1523/jneurosci.4171-05.2006
Goyal R, Angermann JE, Ostrovskaya O, Buchholz JN, Smith GD, Wilson SM (2009) Enhanced capacitative calcium entry and sarcoplasmic-reticulum calcium storage capacity with advanced age in murine mesenteric arterial smooth muscle cells. Exp Gerontol 44(3):201–207. doi:10.1016/j.exger.2008.10.007
Gros R, Van Wert R, You X, Thorin E, Husain M (2002) Effects of age, gender, and blood pressure on myogenic responses of mesenteric arteries from C57BL/6 mice. Am J Physiol Heart Circ Physiol 282(1):H380–H388
Jiang MT, Moffat MP, Narayanan N (1993) Age-related alterations in the phosphorylation of sarcoplasmic reticulum and myofibrillar proteins and diminished contractile response to isoproterenol in intact rat ventricle. Circ Res 72(1):102–111
Jiang MT, Narayanan N (1990) Effects of aging on phospholamban phosphorylation and calcium transport in rat cardiac sarcoplasmic reticulum. Mech Ageing Dev 54(1):87–101
Kinnear NP, Boittin F-X, Thomas JM, Galione A, Evans AM (2004) Lysosome-sarcoplasmic reticulum junctions. J Biol Chem 279(52):54319–54326. doi:10.1074/jbc.M406132200
Knaus HG, Moshammer T, Friedrich K, Kang HC, Haugland RP, Glossman H (1992) In vivo labeling of L-type Ca2+ channels by fluorescent dihydropyridines: evidence for a functional, extracellular heparin-binding site. Proc Natl Acad Sci U S A 89(8):3586–3590
Lee CK, Allison DB, Brand J, Weindruch R, Prolla TA (2002) Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci U S A 99(23):14988–14993. doi:10.1073/pnas.232308999
Lehnart SE, Huang F, Marx SO, Marks AR (2003) Immunophilins and coupled gating of ryanodine receptors. Curr Top Med Chem 3(12):1383–1391
Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS (2008) Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454 (7203):538-542. doi:http://www.nature.com/nature/journal/v454/n7203/suppinfo/nature07065_S1.html
Macrez-Lepretre N, Kalkbrenner F, Schultz G, Mironneau J (1997) Distinct functions of Gq and G11 proteins in coupling alpha1-adrenoreceptors to Ca2+ release and Ca2+ entry in rat portal vein myocytes. J Biol Chem 272(8):5261–5268
Macrez N, Morel JL, Mironneau J (1999) Specific galpha11beta3gamma5 protein involvement in endothelin receptor-induced phosphatidylinositol hydrolysis and Ca2+ release in rat portal vein myocytes. Mol Pharmacol 55(4):684–692
Marijic J, Li Q, Song M, Nishimaru K, Stefani E, Toro L (2001) Decreased expression of voltage- and Ca2+ -activated K + channels in coronary smooth muscle during aging. Circ Res 88(2):210–216. doi:10.1161/01.res.88.2.210
Michaelis ML, Bigelow DJ, Schoneich C, Williams TD, Ramonda L, Yin D, Huhmer AF, Yao Y, Gao J, Squier TC (1996) Decreased plasma membrane calcium transport activity in aging brain. Life Sci 59(5–6):405–412
Miyakawa T, Maeda A, Yamazawa T, Hirose K, Kurosaki T, Iino M (1999) Encoding of Ca2+ signals by differential expression of IP3 receptor subtypes. EMBO J 18(5):1303–1308. doi:10.1093/emboj/18.5.1303
Moore A, Mangoni AA, Lyons D, Jackson SH (2003) The cardiovascular system. Br J Clin Pharmacol 56(3):254–260
Morel JL, Dabertrand F, Fritz N, Henaff M, Mironneau J, Macrez N (2009) The decrease of expression of ryanodine receptor sub-type 2 is reversed by gentamycin sulphate in vascular myocytes from mdx mice. J Cell Mol Med 13(9B):3122–3130. doi:10.1111/j.1582-4934.2009.00718.x
Morel JL, Fritz N, Lavie JL, Mironneau J (2003) Crucial role of type 2 inositol 1,4,5-trisphosphate receptors for acetylcholine-induced Ca2+ oscillations in vascular myocytes. Arterioscler Thromb Vasc Biol 23(9):1567–1575. doi:10.1161/01.ATV.0000089013.82552.5D
Morel JL, Macrez-Lepretre N, Mironneau J (1996) Angiotensin II-activated Ca2+ entry-induced release of Ca2+ from intracellular stores in rat portal vein myocytes. Br J Pharmacol 118(1):73–78
Nelson MT, Standen NB, Brayden JE, Worley JF 3rd (1988) Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature 336(6197):382–385. doi:10.1038/336382a0
Newton CL, Mignery GA, Sudhof TC (1994) Co-expression in vertebrate tissues and cell lines of multiple inositol 1,4,5-trisphosphate (InsP3) receptors with distinct affinities for InsP3. J Biol Chem 269(46):28613–28619
Norris CM, Halpain S, Foster TC (1998) Reversal of age-related alterations in synaptic plasticity by blockade of L-type Ca2+ channels. J Neurosci Off J Soc Neurosci 18(9):3171–3179
O’Connell K, Gannon J, Doran P, Ohlendieck K (2008) Reduced expression of sarcalumenin and related Ca2+ -regulatory proteins in aged rat skeletal muscle. Exp Gerontol 43(10):958–961. doi:10.1016/j.exger.2008.07.006
Palty R, Raveh A, Kaminsky I, Meller R, Reuveny E (2012) SARAF Inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell 149(2):425–438. doi:10.1016/j.cell.2012.01.055
Park S-K, Kim K, Page GP, Allison DB, Weindruch R, Prolla TA (2009) Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants. Aging Cell 8(4):484–495. doi:10.1111/j.1474-9726.2009.00496.x
Pereira GJS, Hirata H, Fimia GM, do Carmo LG, Bincoletto C, Han SW, Stilhano RS, Ureshino RP, Bloor-Young D, Churchill G, Piacentini M, Patel S, Smaili SS (2011) Nicotinic acid adenine dinucleotide phosphate (NAADP) regulates autophagy in cultured astrocytes. J Biol Chem 286(32):27875–27881. doi:10.1074/jbc.C110.216580
Prestle J, Janssen PML, Janssen AP, Zeitz O, Lehnart SE, Bruce L, Smith GL, Hasenfuss G (2001) Overexpression of FK506-binding protein FKBP12.6 in cardiomyocytes reduces ryanodine receptor-ediated Ca2+ leak from the sarcoplasmic reticulum and increases contractility. Circ Res 88(2):188–194. doi:10.1161/01.res.88.2.188
Shehadeh LA, Webster KA, Hare JM, Vazquez-Padron RI (2011) Dynamic regulation of vascular myosin light chain (MYL9) with injury and aging. PLoS One 6(10):e25855. doi:10.1371/journal.pone.0025855
Shen WW, Frieden M, Demaurex N (2011) Remodelling of the endoplasmic reticulum during store-operated calcium entry. Biol Cell 103(8):365–380. doi:10.1042/BC20100152
Shipley RD, Muller-Delp JM (2005) Aging decreases vasoconstrictor responses of coronary resistance arterioles through endothelium-dependent mechanisms. Cardiovasc Res 66(2):374–383. doi:10.1016/j.cardiores.2004.11.005
Smith EG, Voyles WF, Kirby BS, Markwald RR, Dinenno FA (2007) Ageing and leg postjunctional α-adrenergic vasoconstrictor responsiveness in healthy men. J Physiol 582(1):63–71. doi:10.1113/jphysiol.2007.130591
Sugawara H, Kurosaki M, Takata M, Kurosaki T (1997) Genetic evidence for involvement of type 1, type 2 and type 3 inositol 1,4,5-trisphosphate receptors in signal transduction through the B-cell antigen receptor. EMBO J 16(11):3078–3088. doi:10.1093/emboj/16.11.3078
Thai TL, Churchill GC, Arendshorst WJ (2009) NAADP receptors mediate calcium signaling stimulated by endothelin-1 and norepinephrine in renal afferent arterioles. Am J Physiol Ren Physiol 297(2):F510–F516. doi:10.1152/ajprenal.00116.2009
Thibault O, Hadley R, Landfield PW (2001) Elevated postsynaptic [Ca2+]i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J Neurosci Off J Soc Neurosci 21(24):9744–9756
Thibault O, Landfield PW (1996) Increase in single L-type calcium channels in hippocampal neurons during aging. Science 272(5264):1017–1020
Tiwari S, Zhang Y, Heller J, Abernethy DR, Soldatov NM (2006) Atherosclerosis-related molecular alteration of the human CaV1.2 calcium channel α1C subunit. Proc Natl Acad Sci 103(45):17024–17029. doi:10.1073/pnas.0606539103
Uhlén P, Fritz N (2010) Biochemistry of calcium oscillations. Biochem Biophys Res Commun 396(1):28–32. doi:10.1016/j.bbrc.2010.02.117
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034
Walseth TF, Lin-Moshier Y, Jain P, Ruas M, Parrington J, Galione A, Marchant JS, Slama JT (2012) Photoaffinity labeling of high affinity nicotinic acid adenine dinucleotide phosphate (NAADP)-binding proteins in sea urchin egg. J Biol Chem 287(4):2308–2315. doi:10.1074/jbc.M111.306563
Weindruch R, Kayo T, Lee CK, Prolla TA (2002) Gene expression profiling of aging using DNA microarrays. Mech Ageing Dev 123(2–3):177–193
Yamazaki D, Komazaki S, Nakanishi H, Mishima A, Nishi M, Yazawa M, Yamazaki T, Taguchi R, Takeshima H (2009) Essential role of the TRIC-B channel in Ca2+ handling of alveolar epithelial cells and in perinatal lung maturation. Development 136(14):2355–2361. doi:10.1242/dev.036798
Yamazaki D, Tabara Y, Kita S, Hanada H, Komazaki S, Naitou D, Mishima A, Nishi M, Yamamura H, Yamamoto S, Kakizawa S, Miyachi H, Yamamoto S, Miyata T, Kawano Y, Kamide K, Ogihara T, Hata A, Umemura S, Soma M, Takahashi N, Imaizumi Y, Miki T, Iwamoto T, Takeshima H (2011) TRIC-A channels in vascular smooth muscle contribute to blood pressure maintenance. Cell Metab 14(2):231–241. doi:10.1016/j.cmet.2011.05.011
Zhang F, Xia M, Li P-L (2010) Lysosome-dependent Ca2+ release response to Fas activation in coronary arterial myocytes through NAADP: evidence from CD38 gene knockouts. Am J Physiol Cell Physiol 298(5):C1209–C1216. doi:10.1152/ajpcell.00533.2009
Zhao X, Yamazaki D, Park KH, Komazaki S, Tjondrokoesoemo A, Nishi M, Lin P, Hirata Y, Brotto M, Takeshima H, Ma J (2010) Ca2+ Overload and sarcoplasmic reticulum instability in TRIC-A null skeletal muscle. J Biol Chem 285(48):37370–37376. doi:10.1074/jbc.M110.170084
Zhong J, Chen J, Cao T, Wang L, Zhang W, Liu D, Zhu Z (2009) Adenovirus-mediated FKBP12.6 overexpression induces hypertrophy and apoptosis in cultured neonatal cardiomyocytes. Clin Exp Pharmacol Physiol 36(2):135–140. doi:10.1111/j.1440-1681.2008.05030.x
Zhu MX, Ma J, Parrington J, Calcraft PJ, Galione A, Evans AM (2010) Calcium signaling via two-pore channels: local or global, that is the question. Am J Physiol Cell Physiol 298(3):C430–C441. doi:10.1152/ajpcell.00475.2009
Acknowledgments
CGC has performed RT-qPCR experiments, fluorescent pharmacology, and Ca2+ measurements; CM has performed contraction experiments, supervised experiments, and interpretation of results; and JLM and AP wrote the manuscript. We thank A. Joutel for a helpful discussion; D. Berracochea who gave us old mice to initiate the project; A. Donadieu and N. Biendon for technical assistance; and M. Goillandeau for software development (IMN software facilities). The study was supported by grants from the Centre National des Etudes Spatiales, from CNRS (longevity and aging specific action), and Agence Nationale pour la Recherche (AdapHyG no. ANR-09-BLAN-0148) and Region Aquitaine (CGC doctoral fellowship and confocal microscope).
Conflict of interest
There is no conflict of interest with funding providers.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Georgeon-Chartier, C., Menguy, C., Prévot, A. et al. Effect of aging on calcium signaling in C57Bl6J mouse cerebral arteries. Pflugers Arch - Eur J Physiol 465, 829–838 (2013). https://doi.org/10.1007/s00424-012-1195-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-012-1195-7