1932

Abstract

Pericytes, attached to the surface of capillaries, play an important role in regulating local blood flow. Using optogenetic tools and genetically encoded reporters in conjunction with confocal and multiphoton imaging techniques, the 3D structure, anatomical organization, and physiology of pericytes have recently been the subject of detailed examination. This work has revealed novel functions of pericytes and morphological features such as tunneling nanotubes in brain and tunneling microtubes in heart. Here, we discuss the state of our current understanding of the roles of pericytes in blood flow control in brain and heart, where functions may differ due to the distinct spatiotemporal metabolic requirements of these tissues. We also outline the novel concept of electro-metabolic signaling, a universal mechanistic framework that links tissue metabolic state with blood flow regulation by pericytes and vascular smooth muscle cells, with capillary K and Kir2.1 channels as primary sensors. Finally, we present major unresolved questions and outline how they can be addressed.

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2023-02-10
2024-10-05
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Literature Cited

  1. 1.
    Eberth C. 1871. Handbuch der Lehre von der Gewegen des Menschen und der Tiere. Vol. 1 Leipzig, Ger.: Engelmann
    [Google Scholar]
  2. 2.
    Rouget C. 1873. Mémoire sur le développement, la structure et les proprietés physiologiques des capillaires sanguins et lymphatiques. Arch. Physiol. Norm. Pathol. 5:603–63
    [Google Scholar]
  3. 3.
    Zimmermann KW. 1923. Der feinere Bau der Blutcapillaren. Z. Anat. Entwicklungsgesch. 68:129–109
    [Google Scholar]
  4. 4.
    Krogh A. 1920. A contribution to the physiology of the capillaries Nobel Lecture Dec. 11. https://www.nobelprize.org/prizes/medicine/1920/krogh/lecture/
    [Google Scholar]
  5. 5.
    Feigl EO. 1983. Coronary physiology. Physiol. Rev. 63:11–205
    [Google Scholar]
  6. 6.
    DeFily DV, Chilian WM. 1995. Coronary microcirculation: autoregulation and metabolic control. Basic Res. Cardiol. 90:2112–18
    [Google Scholar]
  7. 7.
    Goodwill AG, Dick GM, Kiel AM, Tune JD. 2017. Regulation of coronary blood flow. Compr. Physiol. 7:2321–82
    [Google Scholar]
  8. 8.
    Grainger N, Guarina L, Cudmore RH, Santana LF. 2021. The organization of the sinoatrial node microvasculature varies regionally to match local myocyte excitability. Function 2:4zqab031
    [Google Scholar]
  9. 9.
    Grainger N, Santana LF. 2020. Metabolic-electrical control of coronary blood flow. PNAS 117:158231–33
    [Google Scholar]
  10. 10.
    Zhao G, Joca HC, Nelson MT, Lederer WJ. 2020. ATP- and voltage-dependent electro-metabolic signaling regulates blood flow in heart. PNAS 117:137461–70
    [Google Scholar]
  11. 11.
    Iadecola C. 2017. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96:117–42
    [Google Scholar]
  12. 12.
    Attwell D, Buchan AM, Charpak S, Lauritzen M, MacVicar BA, Newman EA. 2010. Glial and neuronal control of brain blood flow. Nature 468:232–43
    [Google Scholar]
  13. 13.
    Ballanyi K, Doutheil J, Brockhaus J. 1996. Membrane potentials and microenvironment of rat dorsal vagal cells in vitro during energy depletion. J. Physiol. 495:Part 3769–84
    [Google Scholar]
  14. 14.
    Longden TA, Dabertrand F, Koide M, Gonzales AL, Tykocki NR et al. 2017. Capillary K+-sensing initiates retrograde hyperpolarization to locally increase cerebral blood flow. Nat. Neurosci. 20:5717–26
    [Google Scholar]
  15. 15.
    Longden TA, Nelson MT. 2015. Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow. Microcirculation 22:3183–96
    [Google Scholar]
  16. 16.
    Díaz-Flores L, Gutiérrez R, García MP, Díaz-Flores L Jr., Valladares F, Madrid JF. 2012. Ultrastructure of myopericytoma: a continuum of transitional phenotypes of myopericytes. Ultrastruct. Pathol. 36:3189–94
    [Google Scholar]
  17. 17.
    Kovacs-Oller T, Ivanova E, Bianchimano P, Sagdullaev BT. 2020. The pericyte connectome: spatial precision of neurovascular coupling is driven by selective connectivity maps of pericytes and endothelial cells and is disrupted in diabetes. Cell Discov. 6:39
    [Google Scholar]
  18. 18.
    Zhang T, Wu DM, Xu G, Puro DG. 2011. The electrotonic architecture of the retinal microvasculature: modulation by angiotensin II. J. Physiol. 589:Part 92383–99
    [Google Scholar]
  19. 19.
    Hariharan A, Robertson CD, Garcia DCG, Longden TA. 2022. Brain capillary pericytes are metabolic sentinels that control blood flow through KATP channel activity. Cell Rep In press
    [Google Scholar]
  20. 20.
    Hartmann DA, Coelho-Santos V, Shih AY 2022. Pericyte control of blood flow across microvascular zones in the central nervous system. Annu. Rev. Physiol. 84:331–54
    [Google Scholar]
  21. 21.
    Hariharan A, Weir N, Robertson C, He L, Betsholtz C, Longden TA. 2020. The ion channel and GPCR toolkit of brain capillary pericytes. Front. Cell. Neurosci. 14:601324
    [Google Scholar]
  22. 22.
    Gould IG, Tsai P, Kleinfeld D, Linninger A. 2017. The capillary bed offers the largest hemodynamic resistance to the cortical blood supply. J. Cereb. Blood Flow Metab. 37:152–68
    [Google Scholar]
  23. 23.
    Bothwell SW, Janigro D, Patabendige A. 2019. Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases. Fluids Barriers CNS 16:19
    [Google Scholar]
  24. 24.
    Partington T, Farmery A. 2014. Intracranial pressure and cerebral blood flow. Anaesth. Intensive Care Med. 15:(4)189–94
    [Google Scholar]
  25. 25.
    Waters J, Smith SJ. 2002. Vesicle pool partitioning influences presynaptic diversity and weighting in rat hippocampal synapses. J. Physiol. 541:3811–23
    [Google Scholar]
  26. 26.
    Wiener SI, Paul CA, Eichenbaum H. 1989. Spatial and behavioral correlates of hippocampal neuronal activity. J. Neurosci. 9:82737–63
    [Google Scholar]
  27. 27.
    Czurkó A, Hirase H, Csicsvari J, Buzsáki G. 1999. Sustained activation of hippocampal pyramidal cells by “space clamping” in a running wheel. Eur. J. Neurosci. 11:1344–52
    [Google Scholar]
  28. 28.
    Hirase H, Czurkó A, Csicsvari J, Buzsáki G. 1999. Firing rate and theta-phase coding by hippocampal pyramidal neurons during “space clamping. .” Eur. J. Neurosci. 11:124373–80
    [Google Scholar]
  29. 29.
    Wang B, Ke W, Guang J, Chen G, Yin L et al. 2016. Firing frequency maxima of fast-spiking neurons in human, monkey, and mouse neocortex. Front. Cell. Neurosci. 10:239
    [Google Scholar]
  30. 30.
    Attwell D, Laughlin SB. 2001. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21:101133–45
    [Google Scholar]
  31. 31.
    Harris JJ, Jolivet R, Attwell D. 2012. Synaptic energy use and supply. Neuron 75:5762–77
    [Google Scholar]
  32. 32.
    Schaeffer S, Iadecola C. 2021. Revisiting the neurovascular unit. Nat. Neurosci. 24:91198–1209
    [Google Scholar]
  33. 33.
    Daneman R, Prat A. 2015. The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 7:1a020412
    [Google Scholar]
  34. 34.
    Namani R, Lanir Y, Lee LC, Kassab GS. 2020. Overview of mathematical modeling of myocardial blood flow regulation. Am. J. Physiol. Heart Circ. Physiol. 318:4H966–75
    [Google Scholar]
  35. 35.
    Jackson WF. 2022. Endothelial ion channels and cell-cell communication in the microcirculation. Front Physiol. 13:805149
    [Google Scholar]
  36. 36.
    Wolff CB. 2007. Normal cardiac output, oxygen delivery and oxygen extraction. Adv. Exp. Med. Biol. 599:169–82
    [Google Scholar]
  37. 37.
    Wolff CB. 2013. Oxygen delivery: the principal role of the circulation. Adv. Exp. Med. Biol. 789:37–42
    [Google Scholar]
  38. 38.
    Jones PA, Scott-Burden T, Gevers W. 1979. Glycoprotein, elastin, and collagen secretion by rat smooth muscle cells. PNAS 76:1353–57
    [Google Scholar]
  39. 39.
    Mecham RP, Madaras J, McDonald JA, Ryan U. 1983. Elastin production by cultured calf pulmonary artery endothelial cells. J. Cell. Physiol. 116:3282–88
    [Google Scholar]
  40. 40.
    Shen Z, Lu Z, Chhatbar PY, O'Herron P, Kara P 2012. An artery-specific fluorescent dye for studying neurovascular coupling. Nat. Methods 9:273–76
    [Google Scholar]
  41. 41.
    Nees S, Weiss DR, Juchem G. 2013. Focus on cardiac pericytes. Pflügers Arch. 465:6779–87
    [Google Scholar]
  42. 42.
    O'Farrell FM, Mastitskaya S, Hammond-Haley M, Freitas F, Wah WR, Attwell D. 2017. Capillary pericytes mediate coronary no-reflow after myocardial ischaemia. eLife 6:e29280
    [Google Scholar]
  43. 43.
    Zhao G, Joca HC, Lederer WJ. 2020. Dynamic measurement and imaging of capillaries, arterioles, and pericytes in mouse heart. J. Vis. Exp. 161:e61566
    [Google Scholar]
  44. 44.
    Haas TL, Duling BR. 1997. Morphology favors an endothelial cell pathway for longitudinal conduction within arterioles. Microvasc. Res. 53:2113–20
    [Google Scholar]
  45. 45.
    Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J. 2015. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87:195–110
    [Google Scholar]
  46. 46.
    Higuchi K, Hashizume H, Aizawa Y, Ushiki T. 2000. Scanning electron microscopic studies of the vascular smooth muscle cells and pericytes in the rat heart. Arch. Histol. Cytol. 63:2115–26
    [Google Scholar]
  47. 47.
    Attwell D, Mishra A, Hall CN, O'Farrell FM, Dalkara T 2016. What is a pericyte?. J. Cereb. Blood Flow Metab. 36:2451–55
    [Google Scholar]
  48. 48.
    Gonzales AL, Klug NR, Moshkforoush A, Lee JC, Lee FK et al. 2020. Contractile pericytes determine the direction of blood flow at capillary junctions. PNAS 117:4327022–33
    [Google Scholar]
  49. 49.
    Grubb S, Cai C, Hald BO, Khennouf L, Murmu RP et al. 2020. Precapillary sphincters maintain perfusion in the cerebral cortex. Nat. Commun. 11:395
    [Google Scholar]
  50. 50.
    He YY, Yu SJ, Cui Y, Du P. 2010. Morphological study on microvasculature of left ventricular wall in infant and adult yaks. Anat. Rec. 293:91519–26
    [Google Scholar]
  51. 51.
    Zambach SA, Cai C, Helms HCC, Hald BO, Dong Y et al. 2021. Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion. PNAS 118:26e2023749118
    [Google Scholar]
  52. 52.
    Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A et al. 2014. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55–60
    [Google Scholar]
  53. 53.
    Grutzendler J, Nedergaard M. 2019. Cellular control of brain capillary blood flow: in vivo imaging veritas. Trends Neurosci. 42:8528–36
    [Google Scholar]
  54. 54.
    Grant RI, Hartmann DA, Underly RG, Berthiaume A-A, Bhat NR, Shih AY. 2019. Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex. J. Cereb. Blood Flow Metab. 39:3411–25
    [Google Scholar]
  55. 55.
    Hartmann DA, Underly RG, Grant RI, Watson AN, Lindner V, Shih AY. 2015. Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics 2:4041402
    [Google Scholar]
  56. 56.
    Hartmann DA, Berthiaume AA, Grant RI, Harrill SA, Koski T et al. 2021. Brain capillary pericytes exert a substantial but slow influence on blood flow. Nat. Neurosci. 24:5633–45
    [Google Scholar]
  57. 57.
    Ratelade J, Klug NR, Lombardi D, Angelim MKSC, Dabertrand F et al. 2020. Reducing hypermuscularization of the transitional segment between arterioles and capillaries protects against spontaneous intracerebral hemorrhage. Circulation 141:2078–94
    [Google Scholar]
  58. 58.
    Vanlandewijck M, He L, Mäe MA, Andrae J, Ando K et al. 2018. A molecular atlas of cell types and zonation in the brain vasculature. Nature 554:7693475–80
    [Google Scholar]
  59. 59.
    He L, Vanlandewijck M, Mäe M, Andrae J, Ando K et al. 2018. Single cell RNAseq of mouse brain and lung vascular and vessel-associated cell types. Sci. Data 5:180160
    [Google Scholar]
  60. 60.
    Litviňuková M, Talavera-López C, Maatz H, Reichart D, Worth CL et al. 2020. Cells of the adult human heart. Nature 588:466–72
    [Google Scholar]
  61. 61.
    Ando K, Tong L, Peng D, Vázquez-Liébanas E, Chiyoda H et al. 2022. KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling. Dev. Cell 57:111383–99.e7
    [Google Scholar]
  62. 62.
    Jaggar JH, Porter VA, Lederer WJ, Nelson MT. 2000. Calcium sparks in smooth muscle. Am. J. Physiol. Cell Physiol. 278:2C235–56
    [Google Scholar]
  63. 63.
    Nelson MT, Cheng H, Rubart M, Santana LF, Bonev AD et al. 1995. Relaxation of arterial smooth muscle by calcium sparks. Science 270:5236633–37
    [Google Scholar]
  64. 64.
    Furstenau M, Lohn M, Ried C, Luft FC, Haller H, Gollasch M. 2000. Calcium sparks in human coronary artery smooth muscle cells resolved by confocal imaging. J. Hypertens. 18:91215–22
    [Google Scholar]
  65. 65.
    Borysova L, Wray S, Eisner DA, Burdyga T. 2013. How calcium signals in myocytes and pericytes are integrated across in situ microvascular networks and control microvascular tone. Cell Calcium 54:3163–74
    [Google Scholar]
  66. 66.
    Chasseigneaux S, Moraca Y, Cochois-Guégan V, Boulay A-C, Gilbert A et al. 2018. Isolation and differential transcriptome of vascular smooth muscle cells and mid-capillary pericytes from the rat brain. Sci. Rep. 8:12272
    [Google Scholar]
  67. 67.
    Berthiaume AA, Grant RI, McDowell KP, Underly RG, Hartmann DA et al. 2018. Dynamic remodeling of pericytes in vivo maintains capillary coverage in the adult mouse brain. Cell Rep. 22:18–16
    [Google Scholar]
  68. 68.
    Alarcon-Martinez L, Yilmaz-Ozcan S, Yemisci M, Schallek J, Kılıç K et al. 2018. Capillary pericytes express α-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection. eLife 7:e34861
    [Google Scholar]
  69. 69.
    Bartoli F, Debant M, Chuntharpursat-Bon E, Evans EL, Musialowski KE et al. 2022. Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity. J. Clin. Investig. 132:5e141775
    [Google Scholar]
  70. 70.
    Joyce NC, Haire MF, Palade GE. 1985. Contractile proteins in pericytes. I. Immunoperoxidase localization of tropomyosin. J. Cell Biol. 100:51379–86
    [Google Scholar]
  71. 71.
    Joyce NC, Haire MF, Palade GE. 1985. Contractile proteins in pericytes. II. Immunocytochemical evidence for the presence of two isomyosins in graded concentrations. J. Cell Biol. 100:51387–95
    [Google Scholar]
  72. 72.
    Nehls V, Drenckhahn D. 1991. Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J. Cell Biol. 113:1147–54
    [Google Scholar]
  73. 73.
    Forbes MS, Rennels ML, Nelson E 1977. Ultrastructure of pericytes in mouse heart. Am. J. Anat. 149:147–70
    [Google Scholar]
  74. 74.
    Lee LL, Khakoo AY, Chintalgattu V. 2021. Cardiac pericytes function as key vasoactive cells to regulate homeostasis and disease. FEBS Open Bio 11:1207–25
    [Google Scholar]
  75. 75.
    Tao YK, Zeng H, Zhang GQ, Chen ST, Xie XJ et al. 2017. Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia. Int J. Cardiol. 236:413–22
    [Google Scholar]
  76. 76.
    Muhl L, Genové G, Leptidis S, Liu J, He L et al. 2020. Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat. Commun. 11:13953
    [Google Scholar]
  77. 77.
    Rolle IG, Crivellari I, Zanello A, Mazzega E, Dalla E et al. 2021. Heart failure impairs the mechanotransduction properties of human cardiac pericytes. J. Mol. Cell. Cardiol. 151:15–30
    [Google Scholar]
  78. 78.
    Anderson BG, Anderson WD. 1980. Microvasculature of the canine heart demonstrated by scanning electron microscopy. Am. J. Anat. 158:2217–27
    [Google Scholar]
  79. 79.
    Tilton RG, Kilo C, Williamson JR. 1979. Pericyte-endothelial relationships in cardiac and skeletal muscle capillaries. Microvasc. Res. 18:3325–35
    [Google Scholar]
  80. 80.
    Shimada T, Kitamura H, Nakamura M. 1992. Three-dimensional architecture of pericytes with special reference to their topographical relationship to microvascular beds. Arch. Histol. Cytol. 55:Suppl.77–85
    [Google Scholar]
  81. 81.
    Errede M, Mangieri D, Longo G, Girolamo F, de Trizio I et al. 2018. Tunneling nanotubes evoke pericyte/endothelial communication during normal and tumoral angiogenesis. Fluids Barriers CNS 15:128
    [Google Scholar]
  82. 82.
    Alarcon-Martinez L, Villafranca-Baughman D, Quintero H, Kacerovsky JB, Dotigny F et al. 2020. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature 585:782391–95
    [Google Scholar]
  83. 83.
    Figueroa XF, Duling BR. 2009. Gap junctions in the control of vascular function. Antioxid. Redox Signal. 11:2251–66
    [Google Scholar]
  84. 84.
    Emerson GG, Segal SS. 2001. Electrical activation of endothelium evokes vasodilation and hyperpolarization along hamster feed arteries. Am. J. Physiol. Heart Circ. Physiol. 280:1H160–67
    [Google Scholar]
  85. 85.
    Little TL, Beyer EC, Duling BR. 1995. Connexin 43 and connexin 40 gap junctional proteins are present in arteriolar smooth muscle and endothelium in vivo. Am. J. Physiol. Heart Circ. Physiol. 268:2H729–39
    [Google Scholar]
  86. 86.
    McGahren ED, Beach JM, Duling BR. 1998. Capillaries demonstrate changes in membrane potential in response to pharmacological stimuli. Am. J. Physiol. Heart Circ. Physiol. 274:1H60–65
    [Google Scholar]
  87. 87.
    Beach JM, McGahren ED, Duling BR. 1998. Capillaries and arterioles are electrically coupled in hamster cheek pouch. Am. J. Physiol. Heart Circ. Physiol. 275:4H1489–96
    [Google Scholar]
  88. 88.
    Hald BO, Welsh DG. 2020. Conceptualizing conduction as a pliant electrical response: Impact of gap junctions and ion channels. Am. J. Physiol. Heart Circ. Physiol. 319:6H1276–89
    [Google Scholar]
  89. 89.
    Emerson GG, Segal SS. 2000. Endothelial cell pathway for conduction of hyperpolarization and vasodilation along hamster feed artery. Circ. Res. 86:194–100
    [Google Scholar]
  90. 90.
    Little TL, Xia J, Duling BR. 1995. Dye tracers define differential endothelial and smooth muscle coupling patterns within the arteriolar wall. Circ. Res. 76:3498–504
    [Google Scholar]
  91. 91.
    Aydin F, Rosenblum WI, Povlishock JT. 1991. Myoendothelial junctions in human brain arterioles. Stroke 22:121592–97
    [Google Scholar]
  92. 92.
    Straub A, Zeigler A, Isakson B. 2014. The myoendothelial junction: connections that deliver the message. Physiology 29:4242–49
    [Google Scholar]
  93. 93.
    Harraz OF, Longden TA, Dabertrand F, Hill-Eubanks D, Nelson MT. 2018. Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion. PNAS 115:15E3569–77
    [Google Scholar]
  94. 94.
    Moshkforoush A, Ashenagar B, Harraz OF, Dabertrand F, Longden TA et al. 2020. The capillary Kir channel as sensor and amplifier of neuronal signals: modeling insights on K+-mediated neurovascular communication. PNAS 117:2816626–37
    [Google Scholar]
  95. 95.
    Sancho M, Klug NR, Mughal A, Koide M, Huerta de la Cruz S et al. 2022. Adenosine signaling activates ATP-sensitive K+ channels in endothelial cells and pericytes in CNS capillaries. Sci. Signal. 15:727eabl5405
    [Google Scholar]
  96. 96.
    Rasmussen R, Nicholas E, Petersen NC, Dietz AG, Xu Q et al. 2019. Cortex-wide changes in extracellular potassium ions parallel brain state transitions in awake behaving mice. Cell Rep. 28:51182–94.e4
    [Google Scholar]
  97. 97.
    Kříž N, Syková E, Ujec E, Vyklický L. 1974. Changes of extracellular potassium concentration induced by neuronal activity in the spinal cord of the cat. J. Physiol. 238:11–15
    [Google Scholar]
  98. 98.
    Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK et al. 2006. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat. Neurosci. 9:111397–1403
    [Google Scholar]
  99. 99.
    Longden TA, Dunn KM, Draheim HJ, Nelson MT, Weston AH, Edwards G. 2011. Intermediate-conductance calcium-activated potassium channels participate in neurovascular coupling. Br. J. Pharmacol. 164:3922–33
    [Google Scholar]
  100. 100.
    Paulson OB, Newman EA. 1987. Does the release of potassium from astrocyte endfeet regulate cerebral blood flow?. Science 237:4817896–98
    [Google Scholar]
  101. 101.
    Girouard H, Bonev AD, Hannah RM, Meredith A, Aldrich RW, Nelson MT. 2010. Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction. PNAS 107:83811–16
    [Google Scholar]
  102. 102.
    Xie LH, John SA, Weiss JN. 2002. Spermine block of the strong inward rectifier potassium channel Kir2.1: dual roles of surface charge screening and pore block. J. Gen. Physiol. 120:153–66
    [Google Scholar]
  103. 103.
    Hansen SB, Tao X, MacKinnon R. 2011. Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2. Nature 477:7365495–98
    [Google Scholar]
  104. 104.
    Ornelas S, Berthiaume AA, Bonney SK, Coelho-Santos V, Underly RG et al. 2021. Three-dimensional ultrastructure of the brain pericyte-endothelial interface. J. Cereb. Blood Flow Metab. 41:92185–2200
    [Google Scholar]
  105. 105.
    Díaz-Flores L, Gutiérrez R, Madrid JF, Varela H, Valladares F et al. 2009. Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol. Histopathol. 24:7909–69
    [Google Scholar]
  106. 106.
    Waters JP, Kluger MS, Graham M, Chang WG, Bradley JR, Pober JS. 2013. In vitro self-assembly of human pericyte-supported endothelial microvessels in three-dimensional coculture: a simple model for interrogating endothelial-pericyte interactions. J. Vasc. Res. 50:4324–31
    [Google Scholar]
  107. 107.
    Davis MJ, Hill MA. 1999. Signaling mechanisms underlying the vascular myogenic response. Physiol. Rev. 79:2387–423
    [Google Scholar]
  108. 108.
    Longden TA, Mughal A, Hennig GW, Harraz OF, Shui B et al. 2021. Local IP3 receptor-mediated Ca2+ signals compound to direct blood flow in brain capillaries. Sci. Adv. 7:30eabh0101
    [Google Scholar]
  109. 109.
    Mishra A, Reynolds JP, Chen Y, Gourine AV, Rusakov DA, Attwell D. 2016. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat. Neurosci. 19:1619–27
    [Google Scholar]
  110. 110.
    Harraz OF, Longden TA, Hill-Eubanks D, Nelson MT. 2018. PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells. eLife 7:e38689
    [Google Scholar]
  111. 111.
    Fernández-Klett F, Offenhauser N, Dirnagl U, Priller J, Lindauer U. 2010. Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain. PNAS 107:5122290–95
    [Google Scholar]
  112. 112.
    Rorsman P, Ashcroft FM. 2018. Pancreatic β-cell electrical activity and insulin secretion: of mice and men. Physiol. Rev. 98:1117–214
    [Google Scholar]
  113. 113.
    Glukhov AV, Uchida K, Efimov IR, Nichols CG. 2013. Functional roles of KATP channel subunits in metabolic inhibition. J. Mol. Cell. Cardiol. 62:90–98
    [Google Scholar]
  114. 114.
    Foster MN, Coetzee WA. 2015. KATP channels in the cardiovascular system. Physiol. Rev. 96:1177–252
    [Google Scholar]
  115. 115.
    Zhao G, Kaplan A, Greiser M, Lederer WJ. 2020. The surprising complexity of KATP channel biology and of genetic diseases. J. Clin. Investig. 130:31112–15
    [Google Scholar]
  116. 116.
    Bonev AD, Nelson MT. 1996. Vasoconstrictors inhibit ATP-sensitive K+ channels in arterial smooth muscle through protein kinase C. J. Gen. Physiol. 108:4315–23
    [Google Scholar]
  117. 117.
    Quayle JM, Nelson MT, Standen NB. 1997. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol. Rev. 77:41165–232
    [Google Scholar]
  118. 118.
    Kleppisch T, Nelson MT. 1995. Adenosine activates ATP-sensitive potassium channels in arterial myocytes via A2 receptors and cAMP-dependent protein kinase. PNAS 92:2612441–45
    [Google Scholar]
  119. 119.
    Drain P, Li L, Wang J 1998. KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit. PNAS 95:2313953–58
    [Google Scholar]
  120. 120.
    Sung MW, Yang Z, Driggers CM, Patton BL, Mostofian B et al. 2021. Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides. PNAS 118:44e2109441118
    [Google Scholar]
  121. 121.
    Davies LM, Purves GI, Barrett-Jolley R, Dart C 2010. Interaction with caveolin-1 modulates vascular ATP-sensitive potassium (KATP) channel activity. J. Physiol. 588:173255–66
    [Google Scholar]
  122. 122.
    Clark JF, Kemp GJ, Radda GK. 1995. The creatine kinase equilibrium, free [ADP] and myosin ATPase in vascular smooth muscle cross-bridges. J. Theor. Biol. 173:2207–11
    [Google Scholar]
  123. 123.
    Innocenti B, Pozzan T, Fasolato C. 1996. Intracellular ADP modulates the Ca2+ release-activated Ca2+ current in a temperature- and Ca2+-dependent way. J. Biol. Chem. 271:158582–87
    [Google Scholar]
  124. 124.
    Yoon HY, Hwang SH, Lee EY, Kim TU, Cho EH, Cho SW. 2001. Effects of ADP on different inhibitory properties of brain glutamate dehydrogenase isoproteins by perphenazine. Biochimie 83:9907–13
    [Google Scholar]
  125. 125.
    Gribble FM, Loussouarn G, Tucker SJ, Zhao C, Nichols CG, Ashcroft FM. 2000. A novel method for measurement of submembrane ATP concentration. J. Biol. Chem. 275:3930046–49
    [Google Scholar]
  126. 126.
    Larcombe-McDouall J, Buttell N, Harrison N, Wray S. 1999. In vivo pH and metabolite changes during a single contraction in rat uterine smooth muscle. J. Physiol. 518:3783–90
    [Google Scholar]
  127. 127.
    Beech DJ, Zhang H, Nakao K, Bolton TB. 1993. K channel activation by nucleotide diphosphates and its inhibition by glibenclamide in vascular smooth muscle cells. Br. J. Pharmacol. 110:2573–82
    [Google Scholar]
  128. 128.
    Silberberg SD, van Breemen C. 1992. A potassium current activated by lemakalim and metabolic inhibition in rabbit mesenteric artery. Pflügers Arch 420:1118–20
    [Google Scholar]
  129. 129.
    Gruetter R, Novotny EJ, Boulware SD, Rothman DL, Mason GF et al. 1992. Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy. PNAS 89:31109–12
    [Google Scholar]
  130. 130.
    De Vries MG, Arseneau LM, Lawson ME, Beverly JL. 2003. Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia. Diabetes 52:112767–73
    [Google Scholar]
  131. 131.
    McNay EC, Sherwin RS. 2004. From artificial cerebro-spinal fluid (aCSF) to artificial extracellular fluid (aECF): microdialysis perfusate composition effects on in vivo brain ECF glucose measurements. J. Neurosci. Methods 132:135–43
    [Google Scholar]
  132. 132.
    McNay EC, Gold PE. 1999. Extracellular glucose concentrations in the rat hippocampus measured by zero-net-flux. J. Neurochem. 72:2785–90
    [Google Scholar]
  133. 133.
    Dunn-Meynell AA, Sanders NM, Compton D, Becker TC, Eiki JI et al. 2009. Relationship among brain and blood glucose levels and spontaneous and glucoprivic feeding. J. Neurosci. 29:217015–22
    [Google Scholar]
  134. 134.
    Abi-Saab WM, Maggs DG, Jones T, Jacob R, Srihari V et al. 2002. Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects: effects of hyperglycemia and hypoglycemia. J. Cereb. Blood Flow Metab. 22:3271–79
    [Google Scholar]
  135. 135.
    Miki T, Liss B, Minami K, Shiuchi T, Saraya A et al. 2001. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat. Neurosci. 4:507–12
    [Google Scholar]
  136. 136.
    Nippert AR, Chiang PP, Del Franco AP, Newman EA. 2022. Astrocyte regulation of cerebral blood flow during hypoglycemia. J. Cereb. Blood Flow Metab. 42:81534–46
    [Google Scholar]
  137. 137.
    Rogers RC, Hermann GE. 2019. Hindbrain astrocytes and glucose counter-regulation. Physiol. Behav. 204:140–50
    [Google Scholar]
  138. 138.
    Mamun AA, Hayashi H, Yamamura A, Nayeem MJ, Sato M. 2020. Hypoxia induces the translocation of glucose transporter 1 to the plasma membrane in vascular endothelial cells. J. Physiol. Sci. 70:144
    [Google Scholar]
  139. 139.
    Carruthers A, Helgerson AL. 1989. The human erythrocyte sugar transporter is also a nucleotide binding protein. Biochemistry 28:218337–46
    [Google Scholar]
  140. 140.
    Heard KS, Fidyk N, Carruthers A. 2000. ATP-dependent substrate occlusion by the human erythrocyte sugar transporter. Biochemistry 39:113005–14
    [Google Scholar]
  141. 141.
    Blodgett DM, De Zutter JK, Levine KB, Karim P, Carruthers A. 2007. Structural basis of GLUT1 inhibition by cytoplasmic ATP. J. Gen. Physiol. 130:2157–68
    [Google Scholar]
  142. 142.
    Lederer WJ, Cheng H, Santana LF, Gomez AM, Rogers TB et al. 1996. Molecular understanding of excitation-contraction coupling and vascular flow control in heart muscle. Tissue Oxygen Deprivation: From Molecular to Integrated Function GG Haddad, G Lister 497–513. New York: Taylor & Francis
    [Google Scholar]
  143. 143.
    Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Günther K, Goedel-Meinen L. 1990. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels. Science 247:49481341–44
    [Google Scholar]
  144. 144.
    Ishibashi Y, Duncker DJ, Zhang J, Bache RJ. 1998. ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise. Circ. Res. 82:3346–59
    [Google Scholar]
  145. 145.
    Sonkusare SK, Dalsgaard T, Bonev AD, Nelson MT. 2016. Inward rectifier potassium (Kir2.1) channels as end-stage boosters of endothelium-dependent vasodilators. J. Physiol. 594:123271–85
    [Google Scholar]
  146. 146.
    Hirunpattarasilp C, Attwell D, Freitas F. 2019. The role of pericytes in brain disorders: from the periphery to the brain. J. Neurochem. 150:6648–65
    [Google Scholar]
  147. 147.
    Cheng J, Korte N, Nortley R, Sethi H, Tang Y, Attwell D. 2018. Targeting pericytes for therapeutic approaches to neurological disorders. Acta Neuropathol. 136:4507–23
    [Google Scholar]
  148. 148.
    Sagare AP, Sweeney MD, Makshanoff J, Zlokovic BV. 2015. Shedding of soluble platelet-derived growth factor receptor-β from human brain pericytes. Neurosci. Lett. 607:97–101
    [Google Scholar]
  149. 149.
    Gonul E, Duz B, Kahraman S, Kayali H, Kubar A, Timurkaynak E. 2002. Early pericyte response to brain hypoxia in cats: an ultrastructural study. Microvasc. Res. 64:1116–19
    [Google Scholar]
  150. 150.
    Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. 2009. Cadasil. Lancet Neurol. 8:7643–53
    [Google Scholar]
  151. 151.
    Ghosh M, Balbi M, Hellal F, Dichgans M, Lindauer U, Plesnila N. 2015. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann. Neurol. 78:6887–900
    [Google Scholar]
  152. 152.
    Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA et al. 2016. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J. Cereb. Blood Flow Metab. 36:1216–27
    [Google Scholar]
  153. 153.
    Baloyannis SJ, Baloyannis IS. 2012. The vascular factor in Alzheimer's disease: a study in Golgi technique and electron microscopy. J. Neurol. Sci. 322:1–2117–21
    [Google Scholar]
  154. 154.
    Korte N, Nortley R, Attwell D. 2020. Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease. Acta Neuropathol. 140:6793–810
    [Google Scholar]
  155. 155.
    Tuominen S, Miao Q, Kurki T, Tuisku S, Pöyhönen M et al. 2004. Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients. Stroke 35:51063–67
    [Google Scholar]
  156. 156.
    Ruchoux M-M, Kalaria RN, Román GC. 2021. The pericyte: a critical cell in the pathogenesis of CADASIL. Cereb. Circ. Cogn. Behav. 2:100031
    [Google Scholar]
  157. 157.
    Dziewulska D, Lewandowska E. 2012. Pericytes as a new target for pathological processes in CADASIL. Neuropathology 32:5515–21
    [Google Scholar]
  158. 158.
    Mäe MA, He L, Nordling S, Vazquez-Liebanas E, Nahar K et al. 2021. Single-cell analysis of blood-brain barrier response to pericyte loss. Circ. Res. 128:4e46–62
    [Google Scholar]
  159. 159.
    Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC, Alzheimer's Dis. Neuroimag. Init. 2016. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat. Commun. 21:711934
    [Google Scholar]
  160. 160.
    Xu J, Begley P, Church SJ, Patassini S, McHarg S et al. 2016. Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer's disease: metabolic basis for dementia. Sci. Rep. 6:27524
    [Google Scholar]
  161. 161.
    Yang AC, Vest RT, Kern F, Lee DP, Agam M et al. 2022. A human brain vascular atlas reveals diverse mediators of Alzheimer's risk. Nature 603:7903885–92
    [Google Scholar]
  162. 162.
    Hinkel R, Howe A, Renner S, Ng J, Lee S et al. 2017. Diabetes mellitus-induced microvascular destabilization in the myocardium. J. Am. Coll. Cardiol. 69:2131–43
    [Google Scholar]
  163. 163.
    Liu Y, Zhang H, Wang S, Guo Y, Fang X et al. 2021. Reduced pericyte and tight junction coverage in old diabetic rats are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction. Am. J. Physiol. Heart Circ. Physiol. 320:2H549–62
    [Google Scholar]
  164. 164.
    Zeng H, He X, Tuo QH, Liao DF, Zhang GQ, Chen JX. 2016. LPS causes pericyte loss and microvascular dysfunction via disruption of Sirt3/angiopoietins/Tie-2 and HIF-2α/Notch3 pathways. Sci. Rep. 6:20931
    [Google Scholar]
  165. 165.
    Rahman FA, d'Almeida S, Zhang T, Asadi M, Bozoglu T et al. 2021. Sphingosine-1-phosphate attenuates lipopolysaccharide-induced pericyte loss via activation of Rho-A and MRTF-A. Thromb. Haemost. 121:3341–50
    [Google Scholar]
  166. 166.
    Lindahl P, Johansson BR, Levéen P, Betsholtz C. 1997. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:5323242–45
    [Google Scholar]
  167. 167.
    Bjarnegård M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S et al. 2004. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131:81847–57
    [Google Scholar]
  168. 168.
    Chintalgattu V, Rees ML, Culver JC, Goel A, Jiffar T et al. 2013. Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity. Sci. Transl. Med. 5:187187ra69
    [Google Scholar]
  169. 169.
    Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C. 1994. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 8:161875–87
    [Google Scholar]
  170. 170.
    Hellström M, Gerhardt H, Kalén M, Li X, Eriksson U et al. 2001. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153:3543–53
    [Google Scholar]
  171. 171.
    Volz KS, Jacobs AH, Chen HI, Poduri A, McKay AS et al. 2015. Pericytes are progenitors for coronary artery smooth muscle. eLife 4:10036
    [Google Scholar]
  172. 172.
    Chen WC, Baily JE, Corselli M, Díaz ME, Sun B et al. 2015. Human myocardial pericytes: multipotent mesodermal precursors exhibiting cardiac specificity. Stem Cells 33:2557–73
    [Google Scholar]
  173. 173.
    Kuppe C, Ibrahim MM, Kranz J, Zhang X, Ziegler S et al. 2021. Decoding myofibroblast origins in human kidney fibrosis. Nature 589:7841281–86
    [Google Scholar]
  174. 174.
    Pham TTD, Park S, Kolluri K, Kawaguchi R, Wang L et al. 2021. Heart and brain pericytes exhibit a pro-fibrotic response after vascular injury. Circ Res. 129:7e141–43
    [Google Scholar]
  175. 175.
    Su H, Zeng H, Liu B, Chen JX. 2020. Sirtuin 3 is essential for hypertension-induced cardiac fibrosis via mediating pericyte transition. J. Cell. Mol. Med. 24:148057–68
    [Google Scholar]
  176. 176.
    Guimarães-Camboa N, Cattaneo P, Sun Y, Moore-Morris T, Gu Y et al. 2017. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20:3345–59.e5
    [Google Scholar]
  177. 177.
    Methner C, Cao Z, Mishra A, Kaul S. 2021. Mechanism and potential treatment of the “no reflow” phenomenon after acute myocardial infarction: role of pericytes and GPR39. Am. J. Physiol. Heart Circ. Physiol. 321:6H1030–41
    [Google Scholar]
  178. 178.
    Su H, Cantrell AC, Zeng H, Zhu SH, Chen JX. 2021. Emerging role of pericytes and their secretome in the heart. Cells 10:3548
    [Google Scholar]
  179. 179.
    Dedkov EI, Oak K, Christensen LP, Tomanek RJ. 2014. Coronary vessels and cardiac myocytes of middle-aged rats demonstrate regional sex-specific adaptation in response to postmyocardial infarction remodeling. Biol. Sex Differ. 5:11
    [Google Scholar]
  180. 180.
    Dabertrand F, Nelson MT, Brayden JE. 2012. Acidosis dilates brain parenchymal arterioles by conversion of calcium waves to sparks to activate BK channels. Circ. Res. 110:2285–94
    [Google Scholar]
  181. 181.
    Ngai AC, Winn HR. 1995. Modulation of cerebral arteriolar diameter by intraluminal flow and pressure. Circ. Res. 77:4832–40
    [Google Scholar]
  182. 182.
    Li Y, Baylie RL, Tavares MJ, Brayden JE. 2014. TRPM4 channels couple purinergic receptor mechanoactivation and myogenic tone development in cerebral parenchymal arterioles. J. Cereb. Blood Flow Metab. 34:101706–14
    [Google Scholar]
  183. 183.
    Rungta RL, Chaigneau E, Osmanski B-F, Charpa S. 2018. Vascular compartmentalization of functional hyperemia from the synapse to the pia. Neuron 99:2362–37
    [Google Scholar]
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