Role of Pericytes in the Initiation and Propagation of Spontaneous Activity in the Microvasculature

  • Hikaru HashitaniEmail author
  • Retsu Mitsui
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1124)


The microvasculature is composed of arterioles, capillaries and venules. Spontaneous arteriolar constrictions reduce effective vascular resistance to enhance tissue perfusion, while spontaneous venular constrictions facilitate the drainage of tissue metabolites by pumping blood. In the venules of visceral organs, mural cells, i.e. smooth muscle cells (SMCs) or pericytes, periodically generate spontaneous phasic constrictions, Ca2+ transients and transient depolarisations. These events arise from spontaneous Ca2+ release from the sarco-endoplasmic reticulum (SR/ER) and the subsequent opening of Ca2+-activated chloride channels (CaCCs). CaCC-dependent depolarisation further activates L-type voltage-dependent Ca2+ channels (LVDCCs) that play a critical role in maintaining the synchrony amongst mural cells. Mural cells in arterioles or capillaries are also capable of developing spontaneous activity. Non-contractile capillary pericytes generate spontaneous Ca2+ transients primarily relying on SR/ER Ca2+ release. Synchrony amongst capillary pericytes depends on gap junction-mediated spread of depolarisations resulting from the opening of either CaCCs or T-type VDCCs (TVDCCs) in a microvascular bed-dependent manner. The propagation of capillary Ca2+ transients into arterioles requires the opening of either L- or TVDCCs again depending on the microvascular bed. Since the blockade of gap junctions or CaCCs prevents spontaneous Ca2+ transients in arterioles and venules but not capillaries, capillary pericytes appear to play a primary role in generating spontaneous activity of the microvasculature unit. Pericytes in capillaries where the interchange of substances between tissues and the circulation takes place may provide the fundamental drive for upstream arterioles and downstream venules so that the microvasculature network functions as an integrated unit.


Microvasculature Pericyte Sarco-endoplasmic reticulum Ca2+ release Ca2+-activated chloride channel Voltage-dependent Ca2+ channel Intercellular coupling 



The authors are grateful for grant support from the Japan Society for Promotion of the Science (JSPS) (Nos. 21659377, 23659763, 26860521, 16K19361).

Supplementary material

Video 14.1

Spontaneous Ca2+ transients and associated constrictions in mural cells. SMCs in a suburothelial venule Venules of the rat bladder develop nearly synchronous spontaneous Ca2+ transients resulting in vasoconstrictions. Note that SMCs in an arteriole run parallel and remain quiescent. Stellate-shaped pericytes in a suburothelial venule of the mouse bladder develop nearly synchronous spontaneous Ca2+ transients and associated vasoconstrictions. Frame rate is 100 ms (AVI 6091 kb)

Video 14.2

Spontaneous Ca2+ transients in NG2-DsRed (+) pericytes of PCAs and capillaries. NG2-DsRed (+) pericytes in a PCA Pre-capillary arterioles (PCA) develop synchronous spontaneous Ca2+ transients. NG2-DsRed (+) pericytes in a capillary generate nearly synchronous spontaneous Ca2+ transients. Frame rate is 100 ms (AVI 1166 kb)

Video 14.3

Propagation of spontaneous Ca2+ transients in pericytes of capillary/PCA network in the bladder suburothelium. NG2-DsRed (+) pericytes in a capillary network fire spontaneous Ca2+ transients that spread one after another from left to right. Capillary pericytes in a PCA-capillary tree fire spontaneous Ca2+ transients that spread into the PCA to trigger nearly synchronous Ca2+ transients within the PCA-capillary tree. Frame rate is 100 ms (AVI 2730 kb)

Video 14.4

Propagation of spontaneous Ca2+ transients in pericytes of myenteric capillary-PCA network in the guinea pig stomach. Pericytes generate nearly synchronous spontaneous Ca2+ transients within a pericyte network in a PCA and branching capillaries. Frame rate is 91 ms. Spontaneous Ca2+ transients generated in pericytes of a PCA Pre-capillary arterioles (PCA) trigger a near-synchronous Ca2+ transient in circumferentially arranged SMCs of an arteriole. Frame rate is 58 ms (AVI 4221 kb)


  1. 1.
    Segal SS, Damon DN, Duling BR. Propagation of vasomotor responses coordinates arteriolar resistances. Am J Phys. 1989;256:H832–7.Google Scholar
  2. 2.
    Segal SS, Duling BR. Conduction of vasomotor responses in arterioles: a role for cell-to-cell coupling? Am J Phys. 1989;256:H838–45.Google Scholar
  3. 3.
    Dietrich HH, Tyml K. Capillary as a communicating medium in the microvasculature. Microvasc Res. 1992;43:87–99.PubMedCrossRefGoogle Scholar
  4. 4.
    Song H, Tyml K. Evidence for sensing and integration of biological signals by the capillary network. Am J Physiol Heart Circ Physiol. 1993;265:H1235–42.CrossRefGoogle Scholar
  5. 5.
    Ellis CG, Wrigley SM, Groom AC. Heterogeneity of red blood cell perfusion in capillary networks supplied by a single arteriole in resting skeletal muscle. Circ Res. 1994;75:357–68.PubMedCrossRefGoogle Scholar
  6. 6.
    Tyml K, Ellis CG, Safranyos RG, Fraser S, Groom AC. Temporal and spatial distributions of red cell velocity in capillaries of resting skeletal muscle, including estimates of red cell transit times. Microvasc Res. 1981;22:14–31.PubMedCrossRefGoogle Scholar
  7. 7.
    Villringer A, Them A, Lindauer U, Einhäupl K, Dirnagl U. Capillary perfusion of the rat brain cortex. An in vivo confocal microscopy study. Circ Res. 1994;75:55–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Fernández-Klett F, Offenhauser N, Dirnagl U, Priller J, Lindauer U. Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain. Proc Natl Acad Sci U S A. 2010;107:22290–5.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O’Farrell FM, Buchan AM, Lauritzen M, Attwell D. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508:55–60.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Mishra A, Reynolds JP, Chen Y, Gourine AV, Rusakov DA, Attwell D. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat Neurosci. 2016;19:1619–27.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature. 2006;443:700–4.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Ishizaki E, Fukumoto M, Puro DG. Functional KATP channels in the rat retinal microvasculature: topographical distribution, redox regulation, spermine modulation and diabetic alteration. J Physiol. 2009;587:2233–53.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Lamb IR, Novielli NM, Murrant CL. Capillary response to skeletal muscle contraction: evidence that redundancy between vasodilators is physiologically relevant during active hyperaemia. J Physiol. 2018;596:1357–72.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Hirst GDS. Neuromuscular transmission in arterioles of guinea-pig submucosa. J Physiol. 1977;273:263–75.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kotecha N, Neild TO. Actions of vasodilator nerves on arteriolar smooth muscle and neurotransmitter release from sympathetic nerves in the guinea-pig small intestine. J Physiol. 1995;489:849–55.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Hashitani H, Suzuki H. K+ channels which contribute to the acetylcholine-induced hyperpolarization in smooth muscle of the guinea-pig submucosal arteriole. J Physiol. 1997;501:319–29.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Dongaonkar RM, Quick CM, Vo JC, Meisner JK, Laine GA, Davis MJ, Stewart RH. Blood flow augmentation by intrinsic venular contraction in vivo. Am J Phys Regul Integr Comp Phys. 2012;302:R1436–42.Google Scholar
  18. 18.
    Levick JR. Capillary filtration-absorption balance reconsidered in light of dynamic extravascular factors. Exp Physiol. 1991;76:825–57.PubMedCrossRefGoogle Scholar
  19. 19.
    Sakurai T, Terui N. Effects of sympathetically induced vasomotion on tissue-capillary fluid exchange. Am J Physiol Heart Circ Physiol. 2006;291:H1761–7.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Hashitani H, Mitsui R, Miwa-Nishimura K, Lam M. Role of capillary pericytes in the integration of spontaneous Ca2+ transients in the suburothelial microvasculature of the mouse bladder. J Physiol. 2018; 596:3531–52PubMedCrossRefGoogle Scholar
  21. 21.
    Hashitani H, Mitsui R, Shimizu Y, Higashi R, Nakamura K. Functional and morphological properties of pericytes in suburothelial venules of the mouse bladder. Br J Pharmacol. 2012;167:1723–36.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Hashitani H, Takano H, Fujita K, Mitsui R, Suzuki H. Functional properties of suburothelial microvessels in the rat bladder. J Urol. 2011;185:2382–91.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Shimizu Y, Mochizuki S, Mitsui R, Hashitani H. Neurohumoral regulation of spontaneous constrictions in suburothelial venules of the rat urinary bladder. Vasc Pharmacol. 2014;60:84–94.CrossRefGoogle Scholar
  24. 24.
    Hashitani H, Mitsui R, Masaki S, Van Helden DF. Pacemaker role of pericytes in generating synchronized spontaneous Ca2+ transients in the myenteric microvasculature of the guinea-pig gastric antrum. Cell Calcium. 2015;58:442–56.PubMedCrossRefGoogle Scholar
  25. 25.
    Mitsui R, Hashitani H. Functional properties of submucosal venules in the rat stomach. Pflugers Arch. 2015;467:1327–42.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Mitsui R, Hashitani H. Mechanisms underlying spontaneous constrictions of postcapillary venules in the rat stomach. Pflugers Arch. 2016;468:279–91.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Mitsui R, Miyamoto S, Takano H, Hashitani H. Properties of submucosal venules in the rat distal colon. Br J Pharmacol. 2013;170:968–77.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Mitsui R, Hashitani H. Properties of synchronous spontaneous Ca2+ transients in the mural cells of rat rectal arterioles. Pflugers Arch. 2017;469:1189–202.PubMedCrossRefGoogle Scholar
  29. 29.
    Aalkjaer C, Nilsson H. Vasomotion: cellular background for the oscillator and for the synchronization of smooth muscle cells. Br J Pharmacol. 2005;144:605–16.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Aalkjær C, Boedtkjer D, Matchkov V. Vasomotion—what is currently thought? Acta Physiol (Oxford). 2011;202:253–69.CrossRefGoogle Scholar
  31. 31.
    Haddock RE, Hill CE. Rhythmicity in arterial smooth muscle. J Physiol. 2005;566:645–56.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Nilsson H, Aalkjaer C. Vasomotion: mechanisms and physiological importance. Mol Interv. 2003;3:79–89.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Jones TW. Discovery that the veins of the bat’s wing (which are furnished with valves) are endowed with rhythmical contractility, and that the onward flow of blood is accelerated by each contraction. Phil Trans R Soc London. 1852;142:131–6.CrossRefGoogle Scholar
  34. 34.
    D’Agrosa LS. Patterns of venous vasomotion in the bat wing. Am J Phys. 1970;218:530–5.CrossRefGoogle Scholar
  35. 35.
    Davis MJ, Shi X, Sikes PJ. Modulation of bat wing venule contraction by transmural pressure changes. Am J Phys. 1992;262:H625–34.Google Scholar
  36. 36.
    Colantuoni A, Bertuglia S, Intaglietta M. The effects of alpha- or beta-adrenergic receptor agonists and antagonists and calcium entry blockers on the spontaneous vasomotion. Microvasc Res. 1984;28:143–58.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Slaaf DW, Tangelder GJ, Teirlinck HC, Reneman RS. Arteriolar vasomotion and arterial pressure reduction in rabbit tenuissimus muscle. Microvasc Res. 1987;33:71–80.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Hundley WG, Renaldo GJ, Levasseur JE, Kontos HA. Vasomotion in cerebral microcirculation of awake rabbits. Am J Phys. 1988;254:H67–71.Google Scholar
  39. 39.
    Fujii K, Heistad DD, Faraci FM. Vasomotion of basilar arteries in vivo. Am J Phys. 1990;258:H1829–34.Google Scholar
  40. 40.
    Bouskela E, Grampp W. Spontaneous vasomotion in hamster cheek pouch arterioles in varying experimental conditions. Am J Phys. 1992;262:H478–85.Google Scholar
  41. 41.
    Fairfax ST, Mauban JR, Hao S, Rizzo MA, Zhang J, Wier WG. Ca2+ signaling in arterioles and small arteries of conscious, restrained, optical biosensor mice. Front Physiol. 2014;5:387.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Haddock RE, Hirst GD, Hill CE. Voltage independence of vasomotion in isolated irideal arterioles of the rat. J Physiol. 2002;540:219–29.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Hill CE, Eade J, Sandow SL. Mechanisms underlying spontaneous rhythmical contractions in irideal arterioles of the rat. J Physiol. 1999;521:507–16.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Duling BR, Gore RW, Dacey RGJ, Damon DN. Methods for isolation, cannulation, and in vitro study of single microvessels. Am J Phys. 1981;241:H108–16.Google Scholar
  45. 45.
    Haddock RE, Hill CE. Differential activation of ion channels by inositol 1,4,5-trisphosphate (IP3)- and ryanodine-sensitive calcium stores in rat basilar artery vasomotion. J Physiol. 2002;545:615–27.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Delgado E, Marques-Neves C, Rocha I, Sales-Luís J, Silva-Carvalho L. Endothelin-1 effects on spontaneous oscillations in choroidal arterioles. Acta Ophthalmol. 2010;88:742–7.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Gustafsson H, Bülow A, Nilsson H. Rhythmic contractions of isolated, pressurized small arteries from rat. Acta Physiol Scand. 1994;152:145–52.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Lamboley M, Schuster A, Bény JL, Meister JJ. Recruitment of smooth muscle cells and arterial vasomotion. Am J Physiol Heart Circ Physiol. 2003;285:H562–9.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Omote M, Kajimoto N, Mizusawa H. The role of endothelium in the phenylephrine-induced oscillatory responses of rabbit mesenteric arteries. Jpn J Pharmacol. 1992;59:37–41.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Griffith TM, Edwards DH. Fractal analysis of role of smooth muscle Ca2+ fluxes in genesis of chaotic arterial pressure oscillations. Am J Phys. 1994;266:H1801–11.Google Scholar
  51. 51.
    Bartlett IS, Crane GJ, Neild TO, Segal SS. Electrophysiological basis of arteriolar vasomotion in vivo. J Vasc Res. 2000;37:568–75.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Gokina NI, Bevan RD, Walters CL, Bevan JA. Electrical activity underlying rhythmic contraction in human pial arteries. Circ Res. 1996;78:148–53.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Morgan KG. Comparison of membrane electrical activity of cat gastric submucosal arterioles and venules. J Physiol. 1983;345:135–47.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Segal SS, Bény JL. Intracellular recording and dye transfer in arterioles during blood flow control. Am J Phys. 1992;263:H1–7.Google Scholar
  55. 55.
    Brekke JF, Jackson WF, Segal SS. Arteriolar smooth muscle Ca2+ dynamics during blood flow control in hamster cheek pouch. J Appl Physiol. 2006;101:307–15.PubMedCrossRefGoogle Scholar
  56. 56.
    Armulik A, Genové G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21:193–215.PubMedCrossRefGoogle Scholar
  57. 57.
    Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T. What is a pericyte? J Cereb Blood Flow Metab. 2016;36:451–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Borysova L, Wray S, Eisner DA, Burdyga T. How calcium signals in myocytes and pericytes are integrated across in situ microvascular networks and control microvascular tone. Cell Calcium. 2013;54:163–74.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron. 2015;87:95–110.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Hughes S, Chan-Ling T. Characterization of smooth muscle cell and pericyte differentiation in the rat retina in vivo. Invest Ophthalmol Vis Sci. 2004;45:2795–806.PubMedCrossRefGoogle Scholar
  61. 61.
    Fujiwara T, Uehara Y. The cytoarchitecture of the wall and the innervation pattern of the microvessels in the rat mammary gland: a scanning electron microscopic observation. Am J Anat. 1984;170:39–54.PubMedCrossRefGoogle Scholar
  62. 62.
    Shimada T, Kitamura H, Nakamura M. Three-dimensional architecture of pericytes with special reference to their topographical relationship to microvascular beds. Arch Histol Cytol. 1992;55(Suppl):77–85.PubMedCrossRefGoogle Scholar
  63. 63.
    Zhang JQ, Nagata K, Iijima T. Scanning electron microscopy and immunohistochemical observations of the vascular nerve plexuses in the dental pulp of rat incisor. Anat Rec. 1998;251:214–20.PubMedCrossRefGoogle Scholar
  64. 64.
    Zhu X, Bergles DE, Nishiyama A. NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development. 2008;135:145–57.PubMedCrossRefGoogle Scholar
  65. 65.
    Matsushita K, Puro DG. Topographical heterogeneity of KIR currents in pericyte-containing microvessels of the rat retina: effect of diabetes. J Physiol. 2006;573:483–95.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Mitsui R, Hashitani H. Immunohistochemical characteristics of suburothelial microvasculature in the mouse bladder. Histochem Cell Biol. 2013;140:189–200.PubMedCrossRefGoogle Scholar
  67. 67.
    Wu DM, Kawamura H, Sakagami K, Kobayashi M, Puro DG. Cholinergic regulation of pericyte-containing retinal microvessels. Am J Physiol Heart Circ Physiol. 2003;284:H2083–90.PubMedCrossRefGoogle Scholar
  68. 68.
    Pallone TL, Huang JM. Control of descending vasa recta pericyte membrane potential by angiotensin II. Am J Physiol Ren Physiol. 2002;282:F1064–74.CrossRefGoogle Scholar
  69. 69.
    Burdyga T, Borysova L. Calcium signalling in pericytes. J Vasc Res. 2014;51:190–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Nehls V, Drenckhahn D. Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J Cell Biol. 1991;113:147–54.PubMedCrossRefGoogle Scholar
  71. 71.
    Grant RI, Hartmann DA, Underly RG, Berthiaume AA, Bhat NR, Shih AY. Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex. J Cereb Blood Flow Metab. 2017. Scholar
  72. 72.
    O’Farrell FM, Mastitskaya S, Hammond-Haley M, Freitas F, Wah WR, Attwell D. Capillary pericytes mediate coronary no-reflow after myocardial ischaemia. elife. 2017;6:e29280.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Alarcon-Martinez L, Yilmaz-Ozcan S, Yemisci M, Schallek J, Kılıç K, Can A, Di Polo A, Dalkara T. Capillary pericytes express α-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection. elife. 2018;7:e34861.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Higuchi K, Hashizume H, Aizawa Y, Ushiki T. Scanning electron microscopic studies of the vascular smooth muscle cells and pericytes in the rat heart. Arch Histol Cytol. 2000;63:115–26.PubMedCrossRefGoogle Scholar
  75. 75.
    Hirschi KK, D’Amore PA. Pericytes in the microvasculature. Cardiovasc Res. 1996;32:687–98.PubMedCrossRefGoogle Scholar
  76. 76.
    Zhang T, Wu DM, Xu GZ, Puro DG. The electrotonic architecture of the retinal microvasculature: modulation by angiotensin II. J Physiol. 2011;589:2383–99.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Colantuoni A, Bertuglia S, Intaglietta M. Variations of rhythmic diameter changes at the arterial microvascular bifurcations. Pflugers Arch. 1985;403:289–95.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Goligorsky MS, Colflesh D, Gordienko D, Moore LC. Branching points of renal resistance arteries are enriched in L-type calcium channels and initiate vasoconstriction. Am J Phys. 1995;268:F251–7.Google Scholar
  79. 79.
    Tykocki NR, Bonev AD, Longden TA, Heppner TJ, Nelson MT. Inhibition of vascular smooth muscle inward-rectifier K+ channels restores myogenic tone in mouse urinary bladder arterioles. Am J Physiol Ren Physiol. 2017;312:F836–47.CrossRefGoogle Scholar
  80. 80.
    Sanders KM, Ward SM, Koh SD. Interstitial cells: regulators of smooth muscle function. Physiol Rev. 2014;94:859–907.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Suzuki H, Takano H, Yamamoto Y, Komuro T, Saito M, Kato K, Mikoshiba K. Properties of gastric smooth muscles obtained from mice which lack inositol trisphosphate receptor. J Physiol. 2000;525:105–11.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Van Helden DF, Imtiaz MS, Nurgaliyeva K, von der Weid P-Y, Dosen PJ. Role of calcium stores and membrane voltage in the generation of slow wave action potentials in guinea-pig gastric pylorus. J Physiol. 2000;524:245–65.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Imtiaz MS, Zhao J, Hosaka K, von der Weid PY, Crowe M, van Helden DF. Pacemaking through Ca2+ stores interacting as coupled oscillators via membrane depolarization. Biophys J. 2007;92:3843–61.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Van Helden DF. Pacemaker potentials in lymphatic smooth muscle of the guinea-pig mesentery. J Physiol. 1993;471:465–79.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Lang RJ, Hashitani H, Tonta MA, Suzuki H, Parkington HC. Role of Ca2+ entry and Ca2+ stores in atypical smooth muscle cell autorhythmicity in the mouse renal pelvis. Br J Pharmacol. 2007;152:1248–59.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Sergeant GP, Hollywood MA, McCloskey KD, McHale NG, Thornbury KD. Role of IP3 in modulation of spontaneous activity in pacemaker cells of rabbit urethra. Am J Phys Cell Physiol. 2001;280:C1349–56.CrossRefGoogle Scholar
  87. 87.
    Hashitani H, Lang RJ. Spontaneous activity in the microvasculature of visceral organs: role of pericytes and voltage-dependent Ca2+ channels. J Physiol. 2016;594:555–65.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Parker I, Ivorra I. Caffeine inhibits inositol trisphosphate-mediated liberation of intracellular calcium in Xenopus oocytes. J Physiol. 1991;433:229–40.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Thomas NL, Williams AJ. Pharmacology of ryanodine receptors and Ca2+-induced Ca2+ release. WIREs Membr Transp Signal. 2012;1:383–97.CrossRefGoogle Scholar
  90. 90.
    Hashitani H, Edwards FR. Spontaneous and neurally activated depolarizations in smooth muscle cells of the guinea-pig urethra. J Physiol. 1999;514:459–70.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    MacMillan D, Chalmers S, Muir TC, McCarron JG. IP3-mediated Ca2+ increases do not involve the ryanodine receptor, but ryanodine receptor antagonists reduce IP3-mediated Ca2+ increases in guinea-pig colonic smooth muscle cells. J Physiol. 2005;569:533–44.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Zhang Q, Cao C, Zhang Z, Wier WG, Edwards A, Pallone TL. Membrane current oscillations in descending vasa recta pericytes. Am J Physiol Ren Physiol. 2008;294:F656–66.CrossRefGoogle Scholar
  93. 93.
    Bradley E, Hollywood MA, Johnston L, Large RJ, Matsuda T, Baba A, McHale NG, Thornbury KD, Sergeant GP. Contribution of reverse Na+-Ca2+ exchange to spontaneous activity in interstitial cells of Cajal in the rabbit urethra. J Physiol. 2006;574:651–61.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Bradley E, Hollywood MA, McHale NG, Thornbury KD, Sergeant GP. Pacemaker activity in urethral interstitial cells is not dependent on capacitative calcium entry. Am J Phys Cell Physiol. 2005;289:C625–32.CrossRefGoogle Scholar
  95. 95.
    Ward SM, Ordog T, Koh SD, Baker SA, Jun JY, Amberg G, Monaghan K, Sanders KM. Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J Physiol. 2000;525:355–61.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Sergeant GP, Bradley E, Thornbury KD, McHale NG, Hollywood MA. Role of mitochondria in modulation of spontaneous Ca2+ waves in freshly dispersed interstitial cells of Cajal from the rabbit urethra. J Physiol. 2008;586:4631–42.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Hashitani H, Lang RJ, Mitsui R, Mabuchi Y, Suzuki H. Distinct effects of CGRP on typical and atypical smooth muscle cells involved in generating spontaneous contractions in the mouse renal pelvis. Br J Pharmacol. 2009;158:2030–45.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Peng H, Matchkov V, Ivarsen A, Aalkjaer C, Nilsson H. Hypothesis for the initiation of vasomotion. Circ Res. 2001;88:810–5.PubMedCrossRefGoogle Scholar
  99. 99.
    Van Helden DF, Imtiaz MS. Ca2+ phase waves: a basis for cellular pacemaking and long-range synchronicity in the guinea-pig gastric pylorus. J Physiol. 2003;548:271–96.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Sakagami K, Wu DM, Puro DG. Physiology of rat retinal pericytes: modulation of ion channel activity by serum-derived molecules. J Physiol. 1999;521:637–50.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Kito Y, Suzuki H. Properties of pacemaker potentials recorded from myenteric interstitial cells of Cajal distributed in the mouse small intestine. J Physiol. 2003;553:803–18.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Zheng H, Park KS, Koh SD, Sanders KM. Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine. Am J Phys Cell Physiol. 2014;306:C705–13.CrossRefGoogle Scholar
  103. 103.
    Lang RJ, Tonta MA, Takano H, Hashitani H. Voltage-operated Ca2+ currents and Ca2+-activated Cl currents in single interstitial cells of the guinea-pig prostate. BJU Int. 2014;114:436–46.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Matsushita K, Fukumoto M, Kobayashi T, Kobayashi M, Ishizaki E, Minami M, Katsumura K, Liao SD, Wu DM, Zhang T, Puro DG. Diabetes-induced inhibition of voltage-dependent calcium channels in the retinal microvasculature: role of spermine. Invest Ophthalmol Vis Sci. 2010;51:5979–90.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Zhang Z, Rhinehart K, Pallone TL. Membrane potential controls calcium entry into descending vasa recta pericytes. Am J Phys Regul Integr Comp Phys. 2002;283:R949–57.Google Scholar
  106. 106.
    Perez-Reyes E. Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev. 2003;83:117–61.PubMedCrossRefGoogle Scholar
  107. 107.
    Hirano Y, Fozzard HA, January CT. Characteristics of L- and T-type Ca2+ currents in canine cardiac Purkinje cells. Am J Phys. 1989;256:H1478–92.Google Scholar
  108. 108.
    Kuo IY, Wölfle SE, Hill CE. T-type calcium channels and vascular function: the new kid on the block? J Physiol. 2011;589:783–95.PubMedCrossRefGoogle Scholar
  109. 109.
    Kuo IY, Ellis A, Seymour VA, Sandow SL, Hill CE. Dihydropyridine-insensitive calcium currents contribute to function of small cerebral arteries. J Cereb Blood Flow Metab. 2010;30:1226–39.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Gustafsson F, Andreasen D, Salomonsson M, Jensen BL, Holstein-Rathlou N. Conducted vasoconstriction in rat mesenteric arterioles: role for dihydropyridine-insensitive Ca2+ channels. Am J Physiol Heart Circ Physiol. 2001;280:H582–90.PubMedCrossRefGoogle Scholar
  111. 111.
    Jensen LJ, Salomonsson M, Jensen BL, Holstein-Rathlou NH. Depolarization-induced calcium influx in rat mesenteric small arterioles is mediated exclusively via mibefradil-sensitive calcium channels. Br J Pharmacol. 2004;142:709–18.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Morita H, Cousins H, Onoue H, Ito Y, Inoue R. Predominant distribution of nifedipine-insensitive, high voltage-activated Ca2+ channels in the terminal mesenteric artery of guinea pig. Circ Res. 1999;85:596–605.PubMedCrossRefGoogle Scholar
  113. 113.
    Hansen PB, Jensen BL, Andreasen D, Skøtt O. Differential expression of T- and L-type voltage-dependent calcium channels in renal resistance vessels. Circ Res. 2001;89:630–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Gomez-Pinilla PJ, Gibbons SJ, Bardsley MR, Lorincz A, Pozo MJ, Pasricha PJ, Van de Rijn M, West RB, Sarr MG, Kendrick ML, Cima RR, Dozois EJ, Larson DW, Ordog T, Farrugia G. Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol. 2009;296:G1370–81.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Hwang SJ, Blair PJ, Britton FC, O’Driscoll KE, Hennig G, Bayguinov YR, Rock JR, Harfe BD, Sanders KM, Ward SM. Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles. J Physiol. 2009;587:4887–904.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Parsons SP, Kunze WA, Huizinga JD. Maxi-channels recorded in situ from ICC and pericytes associated with the mouse myenteric plexus. Am J Phys Cell Physiol. 2012;302:C1055–69.CrossRefGoogle Scholar
  117. 117.
    Dam VS, Boedtkjer DM, Nyvad J, Aalkjaer C, Matchkov V. TMEM16A knockdown abrogates two different Ca2+-activated Cl currents and contractility. Pflugers Arch. 2014;466:1391–409.PubMedCrossRefGoogle Scholar
  118. 118.
    Kito Y, Mitsui R, Ward SM, Sanders KM. Characterization of slow waves generated by myenteric interstitial cells of Cajal of the rabbit small intestine. Am J Physiol Gastrointest Liver Physiol. 2015;308:G378–88.CrossRefGoogle Scholar
  119. 119.
    Cuevas P, Gutierrez-Diaz JA, Reimers D, Dujovny M, Diaz FG, Ausman JI. Pericyte endothelial gap junctions in human cerebral capillaries. Anat Embryol (Berl). 1984;170:155–9.CrossRefGoogle Scholar
  120. 120.
    Zhang Z, Lin H, Cao C, Payne K, Pallone TL. Descending vasa recta endothelial cells and pericytes form mural syncytia. Am J Physiol Ren Physiol. 2014;306:F751–63.CrossRefGoogle Scholar
  121. 121.
    Zhang Z, Payne K, Pallone TL. Syncytial communication in descending vasa recta includes myoendothelial coupling. Am J Physiol Ren Physiol. 2014;307:F41–52.CrossRefGoogle Scholar
  122. 122.
    Zhang Z, Payne K, Pallone TL. Descending vasa recta endothelial membrane potential response requires pericyte communication. PLoS One. 2016;11:e0154948.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Berthiaume AA, Grant RI, McDowell KP, Underly RG, Hartmann DA, Levy M, Bhat NR, Shih AY. Dynamic remodeling of pericytes in vivo maintains capillary coverage in the adult mouse brain. Cell Rep. 2018;22:8–16.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Yamamoto Y, Klemm MF, Edwards FR, Suzuki H. Intercellular electrical communication among smooth muscle and endothelial cells in guinea-pig mesenteric arterioles. J Physiol. 2001;535:181–95.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Kannan MS, Prakash YS, Johnson DE, Sieck GC. Nitric oxide inhibits calcium release from sarcoplasmic reticulum of porcine tracheal smooth muscle cells. Am J Phys. 1997;272:L1–7.Google Scholar
  126. 126.
    Fleming BP, McKinney ME. Adrenergic innervation in the microcirculation of the bat wing. Microvasc Res. 1985;29:387–400.PubMedCrossRefGoogle Scholar
  127. 127.
    Furness JB, Marshall JM. Correlation of the directly observed responses of mesenteric vessels of the rat to nerve stimulation and noradrenaline with the distribution of adrenergic nerves. J Physiol. 1974;239:75–88.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Fu YY, Peng SJ, Lin HY, Pasricha PJ, Tang SC. 3-D imaging and illustration of mouse intestinal neurovascular complex. Am J Physiol Gastrointest Liver Physiol. 2013;304:G1–11.PubMedCrossRefGoogle Scholar
  129. 129.
    Brookes SJ, Steele PA, Costa M. Calretinin immunoreactivity in cholinergic motor neurones, interneurons and vasomotor neurones in the guinea-pig small intestine. Cell Tissue Res. 1991;263:471–81.PubMedCrossRefGoogle Scholar
  130. 130.
    Neild TO, Shen KZ, Surprenant A. Vasodilatation of arterioles by acetylcholine released from single neurones in the guinea-pig submucosal plexus. J Physiol. 1990;420:247–65.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Hamilton NB, Attwell D, Hall CN. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front Neuroenerg. 2010;2:1–14.CrossRefGoogle Scholar
  132. 132.
    Dora KA, Doyle MP, Duling BR. Elevation of intracellular calcium in smooth muscle causes endothelial cell generation of NO in arterioles. Proc Natl Acad Sci U S A. 1997;94:6529–34.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Garland CJ, Bagher P, Powell C, Ye X, Lemmey HAL, Borysova L, Dora KA. Voltage-dependent Ca2+ entry into smooth muscle during contraction promotes endothelium-mediated feedback vasodilation in arterioles. Sci Signal. 2018;10(486):eaal3806.CrossRefGoogle Scholar
  134. 134.
    Tran CH, Taylor MS, Plane F, Nagaraja S, Tsoukias NM, Solodushko V, Vigmond EJ, Furstenhaupt T, Brigdan M, Welsh D. Endothelial Ca2+ wavelets and the induction of myoendothelial feedback. Am J Phys Cell Physiol. 2012;302:C1226–42.CrossRefGoogle Scholar
  135. 135.
    Svenningsen P, Andersen K, Thuesen AD, Shin HS, Vanhoutte PM, Skøtt O, Jensen BL, Hill C, Hansen PB. T-type Ca2+ channels facilitate NO-formation, vasodilatation and NO-mediated modulation of blood pressure. Pflugers Arch. 2014;466:2205–14.PubMedCrossRefGoogle Scholar
  136. 136.
    Longden TA, Dabertrand F, Koide M, Gonzales AL, Tykocki NR, Brayden JE, Hill-Eubanks D, Nelson MT. Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat Neurosci. 2017;20:717–26.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Longden TA, Hill-Eubanks DC, Nelson MT. Ion channel networks in the control of cerebral blood flow. J Cereb Blood Flow Metab. 2016;36:492–512.PubMedCrossRefGoogle Scholar
  138. 138.
    Greenland JE, Brading AF. Urinary bladder blood flow changes during the micturition cycle in a conscious pig. J Urol. 1996;156:1858–61.PubMedCrossRefGoogle Scholar
  139. 139.
    Sarma KP. Microangiography of the bladder in health. Br J Urol. 1981;53:237–40.PubMedCrossRefGoogle Scholar
  140. 140.
    Birder L, Andersson KE. Urothelial signaling. Physiol Rev. 2013;93:653–80.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Matheson PJ, Wilson MA, Garrison RN. Regulation of intestinal blood flow. J Surg Res. 2000;93:182–96.PubMedCrossRefGoogle Scholar
  142. 142.
    Andersson KE, Boedtkjer DB, Forman A. The link between vascular dysfunction, bladder ischemia, and aging bladder dysfunction. Ther Adv Urol. 2017;9:11–27.PubMedCrossRefGoogle Scholar
  143. 143.
    Andersson KE, Nomiya M, Sawada N, Yamaguchi O. Pharmacological treatment of chronic pelvic ischemia. Ther Adv Urol. 2014;6:105–14.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Thurmond P, Yang JH, Azadzoi KM. LUTS in pelvic ischemia: a new concept in voiding dysfunction. Am J Physiol Ren Physiol. 2016;310:F738–43.CrossRefGoogle Scholar
  145. 145.
    Azadzoi KM, Tarcan T, Siroky MB, Krane RJ. Atherosclerosis-induced chronic ischemia causes bladder fibrosis and non-compliance in the rabbit. J Urol. 1999;161:1626–35.PubMedCrossRefGoogle Scholar
  146. 146.
    Yoshida M, Masunaga K, Nagata T, Satoji Y, Shiomi M. The effects of chronic hyperlipidemia on bladder function in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. Neurourol Urodyn. 2010;29:1350–4.PubMedCrossRefGoogle Scholar
  147. 147.
    Britton E, McLaughlin J. Ageing and the gut. Proc Nutr Soc. 2013;72:173–7.PubMedCrossRefGoogle Scholar
  148. 148.
    Westcott EB, Segal SS. Ageing alters perivascular nerve function of mouse mesenteric arteries in vivo. J Physiol. 2013;591:1251–63.PubMedCrossRefGoogle Scholar
  149. 149.
    Meyer C, de Vries G, Davidge ST, Mayes DC. Reassessing the mathematical modeling of the contribution of vasomotion to vascular resistance. J Appl Physiol. 2002;92:888–9.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Bek T, Jeppesen P, Kanters JK. Spontaneous high frequency diameter oscillations of larger retinal arterioles are reduced in type 2 diabetes mellitus. Invest Ophthalmol Vis Sci. 2013;54:636–40.PubMedCrossRefGoogle Scholar
  151. 151.
    Ivanova E, Kovacs-Oller T, Sagdullaev BT. Vascular pericyte impairment and connexin43 gap junction deficit contribute to vasomotor decline in diabetic retinopathy. J Neurosci. 2017;37:7580–94.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, Sakadžić S, Zlokovic BV. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci. 2017;20:406–16.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Lemaster KA, Farid Z, Brock RW, Shrader CD, Goldman D, Jackson DN, Frisbee JC. Altered post-capillary and collecting venular reactivity in skeletal muscle with metabolic syndrome. J Physiol. 2017;595:5159–74.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmüller P, Humbert M, Guignabert C. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation. 2014;129:1586–97.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med. 2009;15:1031–7.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Nakaizumi A, Puro DG. Vulnerability of the retinal microvasculature to hypoxia: role of polyamine-regulated KATP channels. Invest Ophthalmol Vis Sci. 2011;52:9345–52.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Nakaizumi A, Zhang T, Puro DG. The electrotonic architecture of the retinal microvasculature: diabetes-induced alteration. Neurochem Int. 2012;61:948–53.PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Cell Physiology, Graduate School of Medical SciencesNagoya City UniversityNagoyaJapan

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