Central nervous system pericytes in health and disease

Abstract

Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier (BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Structural and molecular pericyte connections within the neurovascular unit.
Figure 2: Origin of pericytes in the CNS.
Figure 3: Pericyte-endothelial signaling.
Figure 4: Pericytes are multi-functional members of the neurovascular unit.
Figure 5: Pericyte loss can trigger primary vascular dysfunction leading to neurodegeneration.

References

  1. 1

    Zlokovic, B.V. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Tsai, P.S. et al. Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels. J. Neurosci. 29, 14553–14570 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Moskowitz, M.A., Lo, E.H. & Iadecola, C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Zlokovic, B.V. New therapeutic targets in the neurovascular pathway in Alzheimer's disease. Neurotherapeutics 5, 409–414 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Zlokovic, B.V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).

    CAS  PubMed  Google Scholar 

  6. 6

    Weiss, N., Miller, F., Cazaubon, S. & Couraud, P.O. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim. Biophys. Acta 1788, 842–857 (2009).

    CAS  PubMed  Google Scholar 

  7. 7

    Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010). This study demonstrates the role of pericytes in the maintenance of the blood-brain barrier and vascular density in vivo during adulthood.

    CAS  PubMed  Google Scholar 

  8. 8

    Daneman, R., Zhou, L., Kebede, A.A. & Barres, B.A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010). This study describes the role of pericytes in the formation of blood-brain barrier in vivo during embryonic development.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Bell, R.D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010). This study not only describes the role of pericytes in maintaining in vivo blood-brain barrier integrity, microvascular density and functional hyperemia during adulthood and brain aging but also shows that a primary loss of pericytes may lead to two parallel pathways of neurodegeneration, blood-brain barrier breakdown and hypoperfusion, which lead to secondary neurodegenerative changes.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Peppiatt, C.M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006). This study demonstrates constriction of pericytes in response to chemical or electrical stimulation, suggesting that active neurons may directly send signals to pericytes to induce local blood flow changes.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Díaz-Flores, L. et al. Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol. Histopathol. 24, 909–969 (2009).

    PubMed  Google Scholar 

  12. 12

    Stratman, A.N., Malotte, K.M., Mahan, R.D., Davis, M.J. & Davis, G.E. Pericyte recruitment during vasculogenic tube assembly stimulates endothelial basement membrane matrix formation. Blood 114, 5091–5101 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Gerhardt, H., Wolburg, H. & Redies, C. N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev. Dyn. 218, 472–479 (2000).

    CAS  PubMed  Google Scholar 

  14. 14

    Li, F. et al. Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev. Cell 20, 291–302 (2011). This study shows the in vivo role of TGF-β and Notch signaling in the cooperative regulation of N-cadherin expression, pericyte-endothelial attachment and the prevention of perinatal hemorrhage.

    CAS  PubMed  Google Scholar 

  15. 15

    Winkler, E.A., Bell, R.D. & Zlokovic, B.V. Lack of smad or notch leads to a fatal game of brain pericyte hopscotch. Dev. Cell 20, 279–280 (2011).

    CAS  PubMed  Google Scholar 

  16. 16

    Bobbie, M.W., Roy, S., Trudeau, K., Munger, S.J. & Simon, A.M. Reduced connexin 43 expression and its effect on the development of vascular lesions in retinas of diabetic mice. Invest. Ophthalmol. Vis. Sci. 51, 3758–3763 (2010).

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Chew, S.S., Johnson, C.S., Green, C.R. & Danesh-Meyer, H.V. Role of connexin43 in central nervous system injury. Exp. Neurol. 225, 250–261 (2010).

    CAS  PubMed  Google Scholar 

  18. 18

    Shepro, D. & Morel, N.M. Pericyte physiology. FASEB J. 7, 1031–1038 (1993).

    CAS  PubMed  Google Scholar 

  19. 19

    Bautch, V.L. & James, J.M. Neurovascular development: the beginning of a beautiful friendship. Cell Adh. Migr. 3, 199–204 (2009).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Etchevers, H.C., Vincent, C., Le Douarin, N.M. & Couly, G.F. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 128, 1059–1068 (2001).

    CAS  PubMed  Google Scholar 

  21. 21

    Korn, J., Christ, B. & Kurz, H. Neuroectodermal origin of brain pericytes and vascular smooth muscle cells. J. Comp. Neurol. 442, 78–88 (2002).

    PubMed  Google Scholar 

  22. 22

    Kurz, H. Cell lineages and early patterns of embryonic CNS vascularization. Cell Adh. Migr. 3, 205–210 (2009).

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Hellström, M., Kalen, M., Lindahl, P., Abramsson, A. & Betsholtz, C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047–3055 (1999).

    PubMed  Google Scholar 

  24. 24

    Abramsson, A. et al. Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev. 21, 316–331 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Stenzel, D. et al. Peripheral mural cell recruitment requires cell-autonomous heparan sulfate. Blood 114, 915–924 (2009).

    CAS  PubMed  Google Scholar 

  26. 26

    Ozerdem, U. & Stallcup, W.B. Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6, 241–249 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Ozerdem, U. & Stallcup, W.B. Pathological angiogenesis is reduced by targeting pericytes via the NG2 proteoglycan. Angiogenesis 7, 269–276 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Stratman, A.N., Schwindt, A.E., Malotte, K.M. & Davis, G.E. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood 116, 4720–4730 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Piquer-Gil, M., Garcia-Verdugo, J.M., Zipancic, I., Sanchez, M.J. & Alvarez-Dolado, M. Cell fusion contributes to pericyte formation after stroke. J. Cereb. Blood Flow Metab. 29, 480–485 (2009).

    CAS  PubMed  Google Scholar 

  30. 30

    Lamagna, C. & Bergers, G. The bone marrow constitutes a reservoir of pericyte progenitors. J. Leukoc. Biol. 80, 677–681 (2006).

    CAS  PubMed  Google Scholar 

  31. 31

    Kokovay, E., Li, L. & Cunningham, L.A. Angiogenic recruitment of pericytes from bone marrow after stroke. J. Cereb. Blood Flow Metab. 26, 545–555 (2006).

    CAS  PubMed  Google Scholar 

  32. 32

    Gaengel, K., Genove, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009). Comprehensive review describing bidirectional endothelial cell–pericyte signal transduction.

    CAS  PubMed  Google Scholar 

  33. 33

    Lindahl, P., Johansson, B.R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997). Pioneering study using pericyte-deficient mice demonstrating microvascular instability and aneurysm formation in embryonic neural tube.

    CAS  PubMed  Google Scholar 

  34. 34

    Tallquist, M.D., French, W.J. & Soriano, P. Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1, e52 (2003).

    PubMed  PubMed Central  Google Scholar 

  35. 35

    Levéen, P. et al. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 8, 1875–1887 (1994).

    PubMed  Google Scholar 

  36. 36

    Soriano, P. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev. 8, 1888–1896 (1994).

    CAS  PubMed  Google Scholar 

  37. 37

    Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Bjarnegård, M. et al. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131, 1847–1857 (2004).

    PubMed  Google Scholar 

  39. 39

    Enge, M. et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. 21, 4307–4316 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Andrae, J., Gallini, R. & Betsholtz, C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 22, 1276–1312 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Abramsson, A., Lindblom, P. & Betsholtz, C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J. Clin. Invest. 112, 1142–1151 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Winkler, E.A., Bell, R.D. & Zlokovic, B.V. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol. Neurodegener. 5, 32 (2010).

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Geraldes, P. et al. Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat. Med. 15, 1298–1306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Sieczkiewicz, G.J. & Herman, I.M. TGF-beta 1 signaling controls retinal pericyte contractile protein expression. Microvasc. Res. 66, 190–196 (2003).

    CAS  PubMed  Google Scholar 

  45. 45

    Lebrin, F., Deckers, M., Bertolino, P. & Ten Dijke, P. TGF-beta receptor function in the endothelium. Cardiovasc. Res. 65, 599–608 (2005).

    CAS  PubMed  Google Scholar 

  46. 46

    Walshe, T.E. et al. TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature. PLoS ONE 4, e5149 (2009).

    PubMed  PubMed Central  Google Scholar 

  47. 47

    Braun, A. et al. Paucity of pericytes in germinal matrix vasculature of premature infants. J. Neurosci. 27, 12012–12024 (2007).

    CAS  PubMed  Google Scholar 

  48. 48

    Vinukonda, G. et al. Effect of prenatal glucocorticoids on cerebral vasculature of the developing brain. Stroke 41, 1766–1773 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Carvalho, R.L.C. et al. Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice. J. Cell Sci. 120, 4269–4277 (2007).

    CAS  PubMed  Google Scholar 

  50. 50

    Van Geest, R.J., Klaassen, I., Vogels, I.M., Van Noorden, C.J. & Schlingemann, R.O. Differential TGF-β signaling in retinal vascular cells: a role in diabetic retinopathy? Invest. Ophthalmol. Vis. Sci. 51, 1857–1865 (2010).

    PubMed  Google Scholar 

  51. 51

    Paik, J.H. et al. Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev. 18, 2392–2403 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Goumans, M.J. et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 21, 1743–1753 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Dohgu, S. et al. Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production. Brain Res. 1038, 208–215 (2005).

    CAS  PubMed  Google Scholar 

  54. 54

    Saunders, W.B. et al. Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3. J. Cell Biol. 175, 179–191 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Saharinen, P. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat. Cell Biol. 10, 527–537 (2008).

    CAS  PubMed  Google Scholar 

  56. 56

    Wakui, S. et al. Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab. Invest. 86, 1172–1184 (2006).

    CAS  PubMed  Google Scholar 

  57. 57

    Jeansson, M. et al. Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J. Clin. Invest. 121, 2278–2289 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Hofmann, J.J. & Iruela-Arispe, M.L. Notch signaling in blood vessels: who is talking to whom about what? Circ. Res. 100, 1556–1568 (2007).

    CAS  PubMed  Google Scholar 

  59. 59

    Liu, H., Kennard, S. & Lilly, B. NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ. Res. 104, 466–475 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Liu, H., Zhang, W., Kennard, S., Caldwell, R.B. & Lilly, B. Notch3 is critical for proper angiogenesis and mural cell investment. Circ. Res. 107, 860–870 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Regan, J.N. & Majesky, M.W. Building a vessel wall with notch signaling. Circ. Res. 104, 419–421 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Stewart, K.S., Zhou, Z., Zweidler-McKay, P. & Kleinerman, E.S. Delta-like ligand 4-Notch signaling regulates bone marrow-derived pericyte/vascular smooth muscle cell formation. Blood 117, 719–726 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Walshe, T.E. et al. Microvascular retinal endothelial and pericyte cell apoptosis in vitro: role of Hedgehog and Notch signaling. Invest. Ophthalmol. Vis. Sci. 52, 4472–4483 (2011).

    CAS  PubMed  Google Scholar 

  64. 64

    Jin, S. et al. Notch signaling regulates platelet-derived growth factor receptor-β expression in vascular smooth muscle cells. Circ. Res. 102, 1483–1491 (2008).

    CAS  PubMed  Google Scholar 

  65. 65

    Quaegebeur, A., Segura, I. & Carmeliet, P. Pericytes: blood-brain barrier safeguards against neurodegeneration? Neuron 68, 321–323 (2010).

    CAS  PubMed  Google Scholar 

  66. 66

    Paul, J., Strickland, S. & Melchor, J.P. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease. J. Exp. Med. 204, 1999–2008 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Chen, B., Cheng, Q., Yang, K. & Lyden, P.D. Thrombin mediates severe neurovascular injury during ischemia. Stroke 41, 2348–2352 (2010).

    CAS  PubMed  Google Scholar 

  68. 68

    Mhatre, M. et al. Thrombin, a mediator of neurotoxicity and memory impairment. Neurobiol. Aging 25, 783–793 (2004).

    CAS  PubMed  Google Scholar 

  69. 69

    Chen, Z.L. & Strickland, S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91, 917–925 (1997).

    CAS  PubMed  Google Scholar 

  70. 70

    Zhong, Z. et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat. Neurosci. 11, 420–422 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Zhong, Z. et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J. Clin. Invest. 119, 3437–3449 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Hellström, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).

    PubMed  PubMed Central  Google Scholar 

  73. 73

    Ballabh, P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr. Res. 67, 1–8 (2010).

    PubMed  PubMed Central  Google Scholar 

  74. 74

    Virgintino, D. et al. An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis. Angiogenesis 10, 35–45 (2007).

    PubMed  Google Scholar 

  75. 75

    Candelario-Jalil, E., Yang, Y. & Rosenberg, G.A. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158, 983–994 (2009).

    CAS  PubMed  Google Scholar 

  76. 76

    Dore-Duffy, P. et al. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc. Res. 60, 55–69 (2000).

    CAS  PubMed  Google Scholar 

  77. 77

    Darland, D.C. et al. Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev. Biol. 264, 275–288 (2003).

    CAS  PubMed  Google Scholar 

  78. 78

    Gerhardt, H. & Betsholtz, C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 314, 15–23 (2003).

    PubMed  Google Scholar 

  79. 79

    Kamouchi, M. et al. Calcium influx pathways in rat CNS pericytes. Brain Res. Mol. Brain Res. 126, 114–120 (2004).

    CAS  PubMed  Google Scholar 

  80. 80

    Hamilton, N.B., Attwell, D. & Hall, C.N. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front. Neuroenergetics 2, 5 (2010).

    PubMed  PubMed Central  Google Scholar 

  81. 81

    Hirase, H., Creso, J., Singleton, M., Bartho, P. & Buzsaki, G. Two-photon imaging of brain pericytes in vivo using dextran-conjugated dyes. Glia 46, 95–100 (2004).

    PubMed  Google Scholar 

  82. 82

    Chow, N. et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc. Natl. Acad. Sci. USA 104, 823–828 (2007).

    CAS  PubMed  Google Scholar 

  83. 83

    Yemisci, M. et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 15, 1031–1037 (2009).

    CAS  PubMed  Google Scholar 

  84. 84

    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. USA 107, 22290–22295 (2010).

    PubMed  Google Scholar 

  85. 85

    Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347–360 (2004).

    CAS  Google Scholar 

  86. 86

    Zachariah, M.A. & Cyster, J.G. Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328, 1129–1135 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Verbeek, M.M., Westphal, J.R., Ruiter, D.J. & de Waal, R.M. T lymphocyte adhesion to human brain pericytes is mediated via very late antigen-4/vascular cell adhesion molecule-1 interactions. J. Immunol. 154, 5876–5884 (1995).

    PubMed  Google Scholar 

  88. 88

    Dore-Duffy, P., Katychev, A., Wang, X. & Van Buren, E. CNS microvascular pericytes exhibit multipotential stem cell activity. J. Cereb. Blood Flow Metab. 26, 613–624 (2006).

    CAS  PubMed  Google Scholar 

  89. 89

    Hammes, H.P., Feng, Y., Pfister, F. & Brownlee, M. Diabetic retinopathy: targeting vasoregression. Diabetes 60, 9–16 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Gariano, R.F. & Gardner, T.W. Retinal angiogenesis in development and disease. Nature 438, 960–966 (2005).

    CAS  PubMed  Google Scholar 

  91. 91

    Hammes, H.P. et al. Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53, 1104–1110 (2004).

    CAS  PubMed  Google Scholar 

  92. 92

    Pfister, F. et al. Retinal overexpression of angiopoietin-2 mimics diabetic retinopathy and enhances vascular damages in hyperglycemia. Acta Diabetol. 47, 59–64 (2010).

    CAS  PubMed  Google Scholar 

  93. 93

    Farkas, E. & Luiten, P.G. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog. Neurobiol. 64, 575–611 (2001).

    CAS  PubMed  Google Scholar 

  94. 94

    Wu, Z. et al. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat. Med. 11, 959–965 (2005).

    CAS  PubMed  Google Scholar 

  95. 95

    Vinters, H.V. et al. Microvasculature in brain biopsy specimens from patients with Alzheimer's disease: an immunohistochemical and ultrastructural study. Ultrastruct. Pathol. 18, 333–348 (1994).

    CAS  PubMed  Google Scholar 

  96. 96

    Wisniewski, H.M., Wegiel, J., Wang, K.C. & Lach, B. Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease. Acta Neuropathol. 84, 117–127 (1992).

    CAS  PubMed  Google Scholar 

  97. 97

    Wilhelmus, M.M. et al. Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells. Am. J. Pathol. 171, 1989–1999 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157–161 (1999).

    CAS  PubMed  Google Scholar 

  99. 99

    Niwa, K. et al. Aβ1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl. Acad. Sci. USA 97, 9735–9740 (2000).

    CAS  PubMed  Google Scholar 

  100. 100

    Bell, R.D. et al. SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells. Nat. Cell Biol. 11, 143–153 (2009).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the US National Institutes of Health (grants R37 AG023084, R37 NS34467 and HL63290) and the Zilkha family for the research support.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Berislav V Zlokovic.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Winkler, E., Bell, R. & Zlokovic, B. Central nervous system pericytes in health and disease. Nat Neurosci 14, 1398–1405 (2011). https://doi.org/10.1038/nn.2946

Download citation

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing