Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain

Nature Neuroscience

Volumn 20, Issue 3, 2017, Pages 406-416

  Kisler, Kassandra ^a   Nelson, Amy R ^a   Rege, Sanket V ^a   Ramanathan, Anita ^a   Wang, Yaoming ^a   Ahuja, Ashim ^a   Lazic, Divna ^a,b   Tsai, Philbert S ^c   Zhao, Zhen ^a   Zhou, Yi ^d   Boas, David A ^e   Sakadžić, Sava ^e   Zlokovic, Berislav V ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^b UNIVERSITY OF BELGRADE   (Serbia)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d THIRD MILITARY MEDICAL UNIVERSITY   (China)

^e MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

OXYGEN; HOMEODOMAIN PROTEIN; MEOX2 PROTEIN, MOUSE; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BRAIN BLOOD FLOW; BRAIN PERICYTE; CONTROLLED STUDY; IN VIVO STUDY; METABOLIC STRESS; MOUSE; NERVE CELL DEGENERATION; NERVE CELL EXCITABILITY; NERVE CELL STIMULATION; NERVE DEGENERATION; NEUROVASCULAR COUPLING; NONHUMAN; STIMULUS RESPONSE; TISSUE OXYGENATION; ANIMAL; BRAIN; CAPILLARY; CELL DEATH; FEMALE; GENETICS; MALE; METABOLISM; NERVE CELL; PATHOLOGY; PATHOPHYSIOLOGY; PERICYTE; PHYSIOLOGICAL STRESS; PHYSIOLOGY; TRANSGENIC MOUSE; VASCULARIZATION; VASODILATATION;

ANIMALS; BRAIN; CAPILLARIES; CELL DEATH; FEMALE; HOMEODOMAIN PROTEINS; MALE; MICE; MICE, TRANSGENIC; NERVE DEGENERATION; NEURONS; OXYGEN; PERICYTES; RECEPTOR, PLATELET-DERIVED GROWTH FACTOR BETA; STRESS, PHYSIOLOGICAL; VASODILATION;

EID: 85010928380     PISSN: 10976256     EISSN: 15461726     Source Type: Journal    
DOI: 10.1038/nn.4489     Document Type: Article

References (60)

1. Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232-243 (2010).
2. Zlokovic, B.V. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 12, 723-738 (2011).
3. Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844-866 (2013).
4. Iadecola, C. & Nedergaard, M. Glial regulation of the cerebral microvasculature. Nat. Neurosci. 10, 1369-1376 (2007).
5. MacVicar, B.A. & Newman, E.A. Astrocyte regulation of blood flow in the brain. Cold Spring Harb. Perspect. Biol. 7, a020388 (2015).
6. Rouget, C. Memoire sur le developpement, la structures et les proprietes des capillaries sanguins et lymphatiques. Arch. Physiol. Norm. Pathol. 5, 603-633 (1873).
7. Armulik, A., Genové, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193-215 (2011).
8. Winkler, E.A., Bell, R.D. & Zlokovic, B.V. Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398-1405 (2011).
9. Sweeney, M.D., Ayyadurai, S. & Zlokovic, B.V. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat. Neurosci. 19, 771-783 (2016).
10. Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557-561 (2010).
11. 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).
12. 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).
13. Peppiatt, C.M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700-704 (2006).
14. Hall, C.N. et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55-60 (2014).
15. Mishra, A. et al. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat. Neurosci. 19, 1619-1627 (2016).
16. 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).
17. Hill, R.A. et al. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87, 95-110 (2015).
18. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347-360 (2004).
19. Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296-302 (2015).
20. Farkas, E. & Luiten, P.G. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog. Neurobiol. 64, 575-611 (2001).
21. Baloyannis, S.J. & Baloyannis, I.S. The vascular factor in Alzheimer's disease: a study in Golgi technique and electron microscopy. J. Neurol. Sci. 322, 117-121 (2012).
22. Sengillo, J.D. et al. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease. Brain Pathol. 23, 303-310 (2013).
23. Halliday, M.R. et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J. Cereb. Blood Flow Metab. 36, 216-227 (2016).
24. Winkler, E.A. et al. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 125, 111-120 (2013).
25. 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).
26. Montagne, A. et al. Brain imaging of neurovascular dysfunction in Alzheimer's disease. Acta Neuropathol. 131, 687-707 (2016).
27. Blinder, P. et al. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat. Neurosci. 16, 889-897 (2013).
28. 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).
29. Kim, T.N. et al. Line-scanning particle image velocimetry: an optical approach for quantifying a wide range of blood flow speeds in live animals. PLoS One 7, e38590 (2012).
30. Hillman, E.M.C. Optical brain imaging in vivo: techniques and applications from animal to man. J. Biomed. Opt. 12, 051402 (2007).
31. Sirotin, Y.B., Hillman, E.M.C., Bordier, C. & Das, A. Spatiotemporal precision and hemodynamic mechanism of optical point spreads in alert primates. Proc. Natl. Acad. Sci. USA 106, 18390-18395 (2009).
32. Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157-161 (1999).
33. Wu, Z. et al. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat. Med. 11, 959-965 (2005).
34. Sakadzić, S. et al. Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue. Nat. Methods 7, 755-759 (2010).
35. Kasischke, K.A. et al. Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions. J. Cereb. Blood Flow Metab. 31, 68-81 (2011).
36. Baraghis, E. et al. Two-photon microscopy of cortical NADH fluorescence intensity changes: correcting contamination from the hemodynamic response. J. Biomed. Opt. 16, 106003 (2011).
37. Dromparis, P. & Michelakis, E.D. Mitochondria in vascular health and disease. Annu. Rev. Physiol. 75, 95-126 (2013).
38. Barros, L.F. Metabolic signaling by lactate in the brain. Trends Neurosci. 36, 396-404 (2013).
39. Ishii, Y. et al. Characterization of neuroprogenitor cells expressing the PDGF beta-receptor within the subventricular zone of postnatal mice. Mol. Cell. Neurosci. 37, 507-518 (2008).
40. Lindahl, P., Johansson, B.R., Levéen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242-245 (1997).
41. 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).
42. Hartmann, D.A. et al. Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics 2, 041402 (2015).
43. Attwell, D., Mishra, A., Hall, C.N., O'Farrell, F.M. & Dalkara, T. What is a pericyte?. J. Cereb. Blood Flow Metab. 36, 451-455 (2016).
44. Winkler, E.A., Sagare, A.P. & Zlokovic, B.V. The pericyte: a forgotten cell type with important implications for Alzheimer's disease?. Brain Pathol. 24, 371-386 (2014).
45. Kawamura, H. et al. Effects of angiotensin II on the pericyte-containing microvasculature of the rat retina. J. Physiol. (Lond.) 561, 671-683 (2004).
46. Yamanishi, S., Katsumura, K., Kobayashi, T. & Puro, D.G. Extracellular lactate as a dynamic vasoactive signal in the rat retinal microvasculature. Am. J. Physiol. Heart Circ. Physiol. 290, H925-H934 (2006).
47. Oishi, K., Kamiyashiki, T. & Ito, Y. Isometric contraction of microvascular pericytes from mouse brain parenchyma. Microvasc. Res. 73, 20-28 (2007).
48. Dai, M., Nuttall, A., Yang, Y. & Shi, X. Visualization and contractile activity of cochlear pericytes in the capillaries of the spiral ligament. Hear. Res. 254, 100-107 (2009).
49. Park, L. et al. Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke 45, 1815-1821 (2014).
50. Takano, T. et al. Astrocyte-mediated control of cerebral blood flow. Nat. Neurosci. 9, 260-267 (2006).
51. Ragan, T. et al. Serial two-photon tomography for automated ex vivo mouse brain imaging. Nat. Methods 9, 255-258 (2012).
52. 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).
53. Brown, C.E., Aminoltejari, K., Erb, H., Winship, I.R. & Murphy, T.H. In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites. J. Neurosci. 29, 1719-1734 (2009).
54. Bell, R.D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512-516 (2012).
55. Harrison, T.C., Sigler, A. & Murphy, T.H. Simple and cost-effective hardware and software for functional brain mapping using intrinsic optical signal imaging. J. Neurosci. Methods 182, 211-218 (2009).
56. Frostig, R.D., Lieke, E.E., Ts'o, D.Y. & Grinvald, A. Cortical functional architecture and local coupling between neuronal activity and the microcirculation revealed by in vivo high-resolution optical imaging of intrinsic signals. Proc. Natl. Acad. Sci. USA 87, 6082-6086 (1990).
57. Shen, Z., Lu, Z., Chhatbar, P.Y., O'Herron, P. & Kara, P. An artery-specific fluorescent dye for studying neurovascular coupling. Nat. Methods 9, 273-276 (2012).
58. Sagare, A.P. et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4, 2932 (2013).
59. Hesterberg, T. Bootstrap. Wiley Interdiscip. Rev. Comput. Stat. 3, 497-526 (2011).
60. Efron, B. & Tibshirani, R. An Introduction to the Bootstrap (Chapman & Hall 1993.)