Development and function of the blood-brain barrier in the context of metabolic control

Frontiers in Neuroscience

Volumn 11, Issue APR, 2017, Pages

  Haddad Tóvolli, Roberta ^a   Dragano, Nathalia R V ^a   Ramalho, Albina F S ^a   Velloso, Licio A ^a  

^a UNIVERSITY OF CAMPINAS   (Brazil)

Author keywords

Blood brain barrier; Development; Hypothalamus; Inflammation; Neurovascular unit; Obesity

Indexed keywords

ASTROCYTE; BLOOD BRAIN BARRIER; BRAIN DEVELOPMENT; BRAIN ENDOTHELIAL CELL; BRAIN METABOLISM; CAPILLARY; ENDOTHELIUM CELL; ENERGY METABOLISM; HUMAN; HYPOTHALAMUS; METABOLIC REGULATION; MICROGLIA; NERVE CELL NETWORK; NEUROVASCULAR COUPLING; NONHUMAN; PERICYTE; REVIEW;

EID: 85019049965     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2017.00224     Document Type: Review

References (139)

1. Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R., and Begley, D. J. (2010). Structure and function of the blood-brain barrier. Neurobiol. Dis. 37, 13-25. doi: 10.1016/j.nbd.2009.07.030
2. Adams, R. H., and Alitalo, K. (2007). Molecular regulation of angiogenesis and lymphangiogenesis. Nat. Rev. Mol. Cell Biol. 8, 464-478. doi: 10.1038/nrm2183
3. Akmayev, I. G., and Popov, A. P. (1977). Morphological aspects of the hypothalamic-hypophyseal system, VII The tanycytes: their relation to the hypophyseal adrenocorticotrophic function, An ultrastructural study. Cell Tissue Res. 180, 263-282. doi: 10.1007/bf00231958
4. Alvarez, J. I., Dodelet-Devillers, A., Kebir, H., Ifergan, I., Fabre, P. J., Terouz, S., Sabbagh, M., et al. (2011). The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727-1731. doi: 10.1126/science.1206936
5. Alvarez, J. I., Katayama, T., and Prat, A. (2013). Glial influence on the blood brain barrier. Glia 61, 1939-1958. doi: 10.1002/glia.22575
6. Andreone, B. J., Lacoste, B., and Gu, C. (2015). Neuronal and vascular interactions. Annu. Rev. Neurosci. 38, 25-46. doi: 10.1146/annurev-neuro-071714-033835
7. Argente-Arizón, P., Freire-Regatillo, A., Argente, J., and Chowen, J. A. (2015). Role of non-neuronal cells in body weight and appetite control. Front. Endocrinol. 6:42. doi: 10.3389/fendo.2015.00042
8. Armulik, A., Genové, G., and Betsholtz, C. (2011). Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell. 21, 193-215. doi: 10.1016/j.devcel.2011.07.001
9. Armulik, A., Genové, G., Mäe, M., Nisancioglu, M. H., Wallgard, E., Niaudet, C., et al. (2010). Pericytes regulate the blood-brain barrier. Nature 468, 557-556. doi: 10.1038/nature09522
10. Bady, I., Marty, N., Dallaporta, M., Emery, M., Gyger, J., Tarussio, D., et al. (2006). Evidence from glut2-null mice that glucose is a criticalphysiological regulator of feeding. Diabetes 55, 988-995. doi: 10.2337/diabetes.55.04.06.db05-1386
11. Balland, E., Dam, J., Langlet, F., Caron, E., Steculorum, S., Messina, A. et al. (2014). Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 19, 293-301. doi: 10.1016/j.cmet.2013.12.015
12. Banks, W. A. (2016). From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery. Nat. Ver. Drug Discov. 15, 275-292. doi: 10.1038/nrd.2015.21
13. Banks, W. A., Jaspan, J. B., and Kastin, A. J. (1997). Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin. Peptides 18, 1577-1584. doi: 10.1016/S0196-9781(97)00238-6
14. Banks, W. A., Kastin, A. J., Huang, W., Jaspan, J. B., and Maness, L. M. (1996). Leptin enters the brain by a saturable system independent of insulin. Peptides 17, 305-311. doi: 10.1016/0196-9781(96)00025-3
15. Bauer, H., Sonnleitner, U., Lametschwandtner, A., Steiner, M., Adam, H., and Bauer, H. C. (1995). Ontogenic expression of the erythroid-type glucose transporter (Glut 1) in the telencephalon of the mouse: correlation to the tightening of the blood-brain barrier. Brain Res. Dev. Brain Res. 86, 317-325. doi: 10.1016/0165-3806(95)00044-E
16. Bell, R. D., Winkler, E. A., Sagare, A. P., Singh, I., LaRue, B., Deane, R., et al. (2010). Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409-427. doi: 10.1016/j.neuron.2010.09.043
17. Bennett, L., Yang, M., Enikolopov, G., and Iacovitti, L. (2009). Circumventricular organs: a novel site of neural stem cells in the adult brain. Mol. Cell. Neurosci. 41, 337-347. doi: 10.1016/j.mcn.2009.04.007
18. Ben-Zvi, A., Lacoste, B., Kur, E., Andreone, B. J., Mayshar, Y., and Yan, H. (2014). Mfsd2ais critical for the formation and function of the blood-brain barrier. Nature 22, 507-511. doi: 10.1038/nature13324
19. Berger, M., Bergers, G., Arnold, B., Hämmerling, G. J., and Ganss, R. (2005). Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. Blood 105, 1094-1101. doi: 10.1182/blood-2004-06-2315
20. Betsholtz, C. (2014). Physiology: double function at the blood-brain barrier. Nature 509, 432-433. doi: 10.1038/nature13339
21. Blanchette, M., and Daneman, R. (2015). Formation and maintenance of the BBB. Mech. Dev. 138, 8-16. doi: 10.1016/j.mod.2015.07.007
22. Boado, R. J., and Pardridge, W. M. (1990). The brain-type glucose transporter mRNA is specifically expressed at the blood-brain barrier. Biochem. Biophys. Res. Commun. 166, 174-179. doi: 10.1016/0006-291X(90)91927-K
23. Bondjers, C., He, L., Takemoto, M., Norlin, J., Asker, N., Hellström, M., et al. (2006). Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. FASEB J. 20, 1703-1705. doi: 10.1096/fj.05-4944fje
24. Bribair, A., Zhang, T., Wang, Z. M., Messi, M. L., Enikolopov, G. N., Mintz, A., et al. (2013). Skeletal muscle pericyte subtypes differ in their differentiation potential. Stem Cell Res. 10, 67-84. doi: 10.1016/j.scr.2012.09.003
25. Cabezas, R., ávila, M., Gonzalez, J., El-Bachá, S., Báez, E., and García-Segura, L. M. (2014). Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease. Front. Cell. Neurosci. 8:211. doi: 10.3389/fncel.2014.00211
26. Campbell, J. N., Macosko, E. Z., Fenselau, H., Pers, T. H., Lyubetskaya, A., Tenen, D., et al. (2017). A molecular census of arcuate hypothalamus and median eminence cell types. Nat. Neurosci. 20, 484-496. doi: 10.1038/nn.4495
27. Carmeliet, P., Ferreira, V., Breier, G., Pollefeyt, S., Kieckens, L., Gersenstein, M., et al. (1996). Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435-439. doi: 10.1038/380435a0
28. Cashion, M. F., Banks, W. A., and Kastin, A. J. (1996). Sequestration of centrally administered insulin by the brain: effects of starvation, aluminum, and TNF-alpha. Horm. Behav. 30, 280-286. doi: 10.1006/hbeh.1996.0034
29. Cavadas, C., Aveleira, C. A., Souza, G. F., and Velloso, L. A. (2016). The pathophysiology of defective proteostasis in the hypothalamus-from obesity to ageing. Nat. Rev. Endocrinol. 12, 723-733. doi: 10.1038/nrendo.2016.107
30. Chow, B. W., and Gu, C. (2015). The molecular constituents of the blood-brain barrier. Trends Neurosci. 38, 598-608. doi: 10.1016/j.tins.2015.08.003
31. Chowen, J. A., Argente-Arizón, P., Freire-Regatillo, A., Frago, L. M., Horvath, T. L., and Argente, J. (2016). The role of astrocytes in the hypothalamic response and adaptation to metabolic signals. Prog Neurobiol. 144, 68-87. doi: 10.1016/j.pneurobio.2016.03.001
32. Collden, G., Balland, E., Parkash, J., Caron, E., Langlet, F., Prevot, V., et al. (2014). Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. Mol. Metab. 4, 15-24. doi: 10.1016/j.molmet.2014.10.003
33. Correale, J., and Villa, A. (2009). Cellular elements of the blood-brain barrier. Neurochem. Res. 34, 2067-2077. doi: 10.1007/s11064-009-0081-y
34. Cullen, M., Elzarrad, M. K., Seaman, S., Zudaire, E., Stevens, J., Yang, M. Y., et al. (2011). GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain-barrier. Proc. Natl. Acad. Sci. U.S.A. 108, 5759-5764. doi: 10.1073/pnas.1017192108
35. da Fonseca, A. C., Matias, D., Garcia, C., Amaral, R., Geraldo, L. H., Freitas, C., et al. (2014). The impact of microglial activation on blood-brain barrier in brain diseases. Front. Cell. Neurosci. 8:362. doi: 10.3389/fncel.2014.00362
36. Daneman, R., Agalliu, D., Zhou, L., Kuhnert, F., Kuo, C. J., and Barres, B. A. (2009). Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 106, 641-646. doi: 10.1073/pnas.0805165106
37. Daneman, R., and Prat, A. (2015). The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 7:a020412. doi: 10.1101/cshperspect.a020412
38. Daneman, R., Zhou, L., Agalliu, D., Cahoy, J. D., Kaushal, A., and Barres, B. A. (2010a). The mouse blood-brain barrier transcriptome: A new resource for understanding the development and function of brain endothelial cells. PLoS ONE 5:e13741. doi: 10.1371/journal.pone.0013741
39. Daneman, R., Zhou, L., Kebede, A. A., and Barres, B. A. (2010b). Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562-566. doi: 10.1038/nature09513
40. Dejana, E., and Vestweber, D. (2013). The role of VE-cadherin in vascular morphogenesis and permeability control. Prog. Mol. Biol. Transl. Sci.116, 119-144. doi: 10.1016/B978-0-12-394311-8.00006-6
41. de Vries, H. E., Kooij, G., Frenkel, D., Georgopoulos, S., Monsonego, A., and Janigro, D. (2012). Inflammatory events at blood-brain barrier in neuroinflammatory and neurodegenerative disorders: implications for clinical disease. Epilepsia 6, 45-52. doi: 10.1111/j.1528-1167.2012.03702.x
42. Dore-Duffy, P., and Cleary, K. (2011). Morphology and properties of pericytes. Methods Mol. Biol. 686, 49-68. doi: 10.1007/978-1-60761-938-3_2
43. Dziegielewska, K. M., Evans, C. A., Malinowska, D. H., Møllgård, K., Reynolds, J. M., Reynolds, M. L., et al. (1979). Studies of the development of brain barrier systems to lipid insoluble molecules in fetal sheep. J. Physiol. 292, 207-231. doi: 10.1113/jphysiol.1979.sp012847
44. Eberth, C. J. (1871). Handbuch der Lehre von der Gewegen des Menschen und der Tiere, Vol. 1. Leipzig: Engelmann
45. Ehrlich, P. (1885). Das Sauerstoff-Bedürfniss des Organismus: eine Farbenanalytische Studie. Berlin: Hirschwald
46. Engelhardt, B., and Liebner, S. (2014). Novel insights into the development and maintenance of the blood-brain barrier. Cell Tissue Res. 355, 687-699. doi: 10.1007/s00441-014-1811-2
47. Fantin, A., Vieira, J. M., Gestri, G., Denti, L., Schwarz, Q., Prykhozhij, S., et al. (2010). Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116, 829-840. doi: 10.1182/blood-2009-12-257832
48. Farrell, C. L., and Pardridge, W. M. (1991). Blood-brain barrier glucose transporter is asym-metrically distributed on brain capillary endothelial lumenal and ablumenalmembranes: an electron microscopic immunogold study. Proc. Natl. Acad. Sci. U.S.A. 88, 5779-5783. doi: 10.1073/pnas.88.13.5779
49. Fenselau, H., Campbell, J. N., Verstegen, A. M., Madara, J. C., Xu, J., Shah, B. P., et al. (2017). A rapidly acting glutamatergic ARC ? PVH satiety circuit postsynaptically regulated by a-MSH. Nat. Neurosci. 20, 42-51. doi: 10.1038/nn.4442
50. Fernández-Klett, F., Offenhauser, N., Dirnagl, U., Priller, J., and Lindauer, U. (2010). Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain. Proc. Natl. Acad. Sci. USA, 107, 22290-22295. doi: 10.1073/pnas.1011321108
51. Frayling, C., Britton, R., and Dale, N. (2011). ATP-mediated glucosensing by hypothalamic tanycytes. J. Physiol. 589(Pt 9), 2275-2286. doi: 10.1113/jphysiol.2010.202051
52. Ganong, W. F. (2000). Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin. Exp. Pharmacol. Physiol. 27, 422-427. doi: 10.1046/j.1440-1681.2000.03259.x
53. Goldmann, E. E. (1909). Dieäussere und innere Sekretion des gesunden und kranken Organismus im Lichte der 'vitalen Färbung.' Beiträg Klinische Chirurgie 64, 192-265
54. Goldmann, E. E. (1913). Vitalfärbung am Zentralnervensyatem. Beitrag zur Physio-Pathologie dês plexus chorioideus und der Hirnhäute. Abh preuss, Akad Wiss Phys-Math Kl 1, 1-60
55. Haan, N., Goodman, T., Najdi-Samiei, A., Stratford, C. M., Rice, R., El Agha, E., et al. (2013). Fgf10-expressing tanycytes add new neurons to the appetite/energy-balance regulating centers of the postnatal and adult hypothalamus. J. Neurosci. 33, 6170-6180. doi: 10.1523/JNEUROSCI.2437-12.2013
56. Hagan N., Ben-Zvi, A. (2015). The molecular, cellular, and morphological components of blood-brain barrier development during embryogenesis. Semin. Cell Biol. 38, 7-15. doi: 10.1016/j.semcdb.2014.12.006
57. Halilagic, A., Ribes, V., Ghyselinck, N. B., Zile, M. H., Dollé, P., and Studer, M. (2007). Retinoids control anterior and dorsal properties in the developing forebrain. Dev Biol. 303, 362-375. doi: 10.1016/j.ydbio.2006.11.021
58. Hall, C. N., Reynell, C., Gesslein, B., Hamilton, N. B., Mishra, A., Sutherland, B. A., et al. (2014). Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55-60. doi: 10.1038/nature13165
59. Havrankova, J., Brownstein, M., and Roth, J. (1981). Insulin and insulin receptors in rodent brain. Diabetologia 20, 268-273. doi: 10.1007/BF00254492
60. Hawkins, R. A., O'Kane, R. L., Simpson, I. A., and Viña, J. R. (2006). Structure of the blood-brain barrier and its role in the transport of amino acids. J. Nutr. 36, 218S-226S
61. Hellstrom, M., Gerhardt, H., Kalén, M., Li, X., Eriksson, U., Wolburg, H., et al. (2001). Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543-553. doi: 10.1083/jcb.153.3.543
62. Hellstrom, M., Kalen, M., Lindahl, P., Abramsson, A., and Betsholtz, C. (1999). Role of PDGF-B and PDGFR-ß in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047-3055
63. Hill, R. A., Tong, L., Yuan, P., Murikinati, S., Gupta, S., and 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, 95-110. doi: 10.1016/j.neuron.2015.06.001
64. Hofmann, K., Lamberz, C., Piotrowitz, K., Offermann, N., But, D., Scheller, A., et al. (2017). Tanycytes and a differential fatty acid metabolism in the hypothalamus. Glia 65, 231-249. doi: 10.1002/glia.23088
65. Holly, J., and Perks, C. (2006). The role of insulin-like growth factor binding proteins. Neuroendocrin 83, 154-160. doi: 10.1159/000095523
66. Janzer, R. C., and Raff, M. C. (1987). Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325, 253-257. doi: 10.1038/325253a0
67. Kastin, A. J., and Akerstrom, V. (2000). Fasting, but not adrenalectomy, reduces transport of leptin into the brain. Peptides 21, 679-682. doi: 10.1016/S0196-9781(00)00195-9
68. Kastin, A. J., Akerstrom, V., and Hackler, L. (2001). Food deprivation decreases blood galanin-like peptide and its rapid entry into the brain. Neuroendocrinology 74, 423-432. doi: 10.1159/000054708
69. Keaney, J., and Campbell, M. (2015). The dynamic blood-brain barrier. FEBS J. 282, 4067-4079. doi: 10.1111/febs.13412
70. Keller, A. (2013). Breaking and building the wall: the biology of the blood-brain barrier in health and disease. Swiss Med. Wkly. 143, 1-9. doi: 10.4414/smw.2013.13892
71. Kim, D. W., Glendining, K. A., Grattan, D. R., and Jasoni, C. L. (2016). Maternal obesity in the mouse compromises the blood-brain barrier in the arcuate nucleus of offspring. Endocrinology 157, 2229-2242. doi: 10.1210/en.2016-1014
72. Kim, J. G., Suyama, S., Koch, M., Jin, S., Argente-Arizon, P., Argente, J., et al. (2014). Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat. Neurosci. 17, 908-910. doi: 10.1038/nn.3725
73. Kuhnert, F., Mancuso, M. R., Shamloo, A., Wang, H. T., Choksi, V., Florek, M., et al. (2010). Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science 330, 985-989. doi: 10.1126/science.1196554
74. Lam, B. Y. H., Cimino, I., Polex-Wolf, J., Kohnke, S. N., Rimmington, D., Iyemere, V., et al. (2017). Heterogeneity of hypothalamic Pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing. Mol. Met. 6, 1-10. doi: 10.1016/j.molmet.2017.02.007
75. Lam, T. K., Schwartz, G. J., and Rossetti, L. (2005). Hypothalamic sensing of fatty acids. Nat. Neurosci. 8, 579-584. doi: 10.1038/nn1456
76. Langlet, F., Levin, B. E., Luquet, S., Mazzone, M., Messina, A., et al. (2013a). Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab. 17, 607-617. doi: 10.1016/j.cmet.2013.03.004
77. Langlet, F., Mullier, A., Bouret, S. G., Prevot, V., and Dehouck, B. (2013b). Tanycyte-like cells form a blood-cerebrospinal fluid barrier in the circumventricular organs of the mouse brain. J. Comp. Neurol. 21, 3389-3405. doi: 10.1002/cne.23355
78. Lee, D. A., Bedont, J. L., Pak, T., Wang, H., Song, J., Miranda-Angulo, A., et al. (2012). Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat. Neurosci. 15, 700-702. doi: 10.1038/nn.3079
79. Lee, S. W., Kim, W. J., Choi, Y. K., Song, H. S., Son, M. J., et al. (2003). SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat. Med. 9, 900-906. doi: 10.1038/nm889
80. Lewandowsky, M. (1900). Zur Lehre von der Cerebrospinalflüssgkeit. Z. Clin. Med. 40, 480-494
81. Lichtensteiger, W., Richards, J. G., and Kopp, H. G. (1978). Changes in the distribution of non-neuronal elements in rat median eminence and in anterior pituitary hormone secretion after activation of tuberoinfundibular dopamine neurones by brain stimulation or nicotine. Brain Res. 157, 73-88. doi: 10.1016/0006-8993(78)90997-6
82. Liebner, S., Corada, M., Bangsow, T., Babbage, J., Taddei, A., Czupalla, C. J., et al. (2008). Wnt/beta-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183, 409-417. doi: 10.1083/jcb.200806024
83. Lindahl, P., Johansson, B. R., Levéen, P., and Betsholtz, C. (1997). Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242-245. doi: 10.1126/science.277.5323.242
84. Lindblom, P., Gerhardt, H., Liebner, S., Abramsson, A., Hellström, M., Bäckström, G., et al. (2003). Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835-1840. doi: 10.1101/gad.266803
85. Luissint, A. C., Artus, C., Glacial, F., Ganeshamoorthy, K., and Couraud, P. O. (2012). Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS 9:23. doi: 10.1186/2045-8118-9-23
86. Lull, M. E., and Block, M. L. (2010). Microglial activation and chronic neurodegeneration. Neurotherapeutics 4, 354-365. doi: 10.1016/j.nurt.2010.05.014
87. Marty, N., Dallaporta, M., Foretz, M., Emery, M., Tarussio, D., Bady, I., et al. (2005). Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocytedependent glucose sensors. J Clin. Invest. 115, 3545-3553. doi: 10.1172/JCI26309
88. Millis, S. J., Cowin, A. J., and Kaur, P. (2013). Pericytes, mesenchymal stem cells and the wound healing process. Cells. 2, 621-634 doi: 10.3390/cells2030621
89. Mitchell, R. W., and Hatch, G. M. (2011). Fatty acid transport into the brain: of fatty acid fables and lipid tails. Prostaglandins Leukot. Essent. Fatty Acids. 85, 293-302. doi: 10.1016/j.plefa.2011.04.007
90. Mizee, M. R., Wooldrik, D., Lakeman, K. A., van het Hof, B., Drexhage, J. A., Geerts, D., et al. (2013). Retinoic acid induces blood-brain barrier development. J. Neurosci 33, 1660-1671. doi: 10.1523/JNEUROSCI.1338-12.2013
91. Mullier, A., Bouret, S. G., Prevot, V., and Dehouck, B. (2010). Differential distribution of tight junction proteins suggests a role for tanycytes in blood-hypothalamus barrier regulation in the adult mouse brain. J. Comp. Neurol. 518, 943-962. doi: 10.1002/cne.22273
92. Nayak, D., Roth, T. L., and McGavern, D. B. (2014). Microglia development and function. Annu. Rev. Immunol. 32, 367-402. doi: 10.1146/annurev-immunol-032713-120240
93. Nishioku, T., Matsumoto, J., Dohgu, S., Sumi, N., Miyao, K., Takata, F., et al. (2010). Tumor necrosis factor-alpha mediates the blood-brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells. J. Pharmacol. Sci. 112, 251-254. doi: 10.1254/jphs.09292SC
94. Obermeier, B., Daneman, R., and Ransohoff, R. M. (2013). Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 19, 1584-1596. doi: 10.1038/nm.3407
95. Obici, S., and Rossetti, L. (2003). Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology144, 5172-5178. doi: 10.1210/en.2003-0999
96. Olsson, A. K., Dimberg, A., Kreuger, J., and Claesson-Welsh, L. (2006). VEGF receptor signalling-in control of vascular function. Nat. Rev. Mol. Cell Biol. 7, 359-371. doi: 10.1038/nrm1911
97. Pam, W., Banks, W. A., Kennedy, M. K., Guiterrez, E. G., and Kastin, A. J. (1996). Differential permeability of the BBB in acute EAE: enhanced transport of TNT-alpha. Am. J. Physiol. 271, E636-E642
98. Pardridge, W. M., Boado, R. J., and Farrell, C. R. (1990). Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. Studies with quantitative western blotting and in situ hybridization. J. Biol Chem. 265, 18035-18040
99. Peppiatt, C. M., Howarth, C., Mobbs, P., and Attwell, D. (2006). Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700-704. doi: 10.1038/nature05193
100. Potente, M., Gerhardt, H., and Carmeliet, P. (2011). Basic and therapeutic aspects of angiogenesis. Cell 146, 873-887. doi: 10.1016/j.cell.2011.08.039
101. Raab, S., Beck, H., Gaumann, A., Yüce, A., Gerber, H. B., Plate, K., et al. (2004). Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb. Haemost. 91, 595-605. doi: 10.1160/th03-09-0582
102. Reese, T. S., and Karnovsky, M. J. (1967). Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34, 207-217. doi: 10.1083/jcb.34.1.207
103. Ribatti, D., Nico, B., Crivellato, E., and Artico, M. (2006). Development of the blood-brain barrier: a historical point of view. Anat. Rec. B New Anat. 289B, 3-8. doi: 10.1002/ar.b.20087
104. Risau, W., Hallmann, R., and Albrecht, U. (1986). Differentiation dependent expression of proteins in brain endothelium during development of the blood-brain barrier. Dev. Biol. 117, 537-545. doi: 10.1016/0012-1606(86)90321-0
105. Rodríguez, E. M., Blázquez, J. L., and Guerra, M. (2010). The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides 31, 757-776. doi: 10.1016/j.peptides.2010.01.003
106. Rouget, C. (1873). Memoire sur le developpement, la structures et les proprietes des capillaires sanguins et lymphatiques. Archs. Physiol. Norm. Pathol. 5, 603-633
107. Rustenhoven, J., Jansson, D., Smyth, L. C., and Dragunow, M. (2016). Brain pericytes as mediators of neuroinflammation. Trends Pharmacol. Sci. 38, 291-304. doi: 10.1016/j.tips.2016.12.001
108. Saijo, K., and Glass, C. K. (2011). Microglial cell origin and phenotypes in health and disease. Nat. Rev. Immunol. 11, 775-787. doi: 10.1038/nri3086
109. Saunders, N. R., Daneman, R., Dziegielewska, K. M., and Liddelow, S. A. (2013). Transporters of the blood-brain and blood-CSF interfaces in development and in the adult. Mol. Aspects Med. 34, 742-752. doi: 10.1016/j.mam.2012.11.006
110. Saunders, N. R., Liddelow, S. A., and Dziegielewska, K. M. (2012). Barrier mechanisms in the developing brain. Front. Pharmacol. 3:46. doi: 10.3389/fphar.2012.00046
111. Shalaby, F., Rossant, J., Yamaguchi, T. P., Gersenstein, M., Wu, X. F., Breitman, M. L., et al. (1995). Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62-66. doi: 10.1038/376062a0
112. Shepro, D., and Morel, N. M. (1993). Pericyte physiology. FASEB J. 7, 1031-1038
113. Siegenthaler, J. A., Sohet, F., and Daneman, R. (2013). 'Sealing off the CNS': cellular and molecular regulation of blood-brain barriergenesis. Curr. Opin. Neurobiol. 23, 1057-1064. doi: 10.1016/j.conb.2013.06.006
114. Sofroniew, M. V., and Vinters, H. V. (2010). Astrocytes: biology and pathology Acta Neuropathol. 119, 7-35. doi: 10.1007/s00401-009-0619-8
115. Stenman, J. M., Rajagopal, J., Carroll, T. J., Ishibashi, M., McMahon, J., and McMahon, A. P. (2008). Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247-1250. doi: 10.1126/science.1164594
116. Stolarczyk, E., Guissard, C., Michau, A., Even, P. C., Grosfeld, A., Serradas, P., et al. (2010). Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake. Am J Physiol Endocrinol. Metab. 298, E1078-E1087. doi: 10.1152/ajpendo.00737.2009
117. Sumi, N., Nishioku, T., Takata, F., Matsumoto, J., Watanabe, T., Shuto, H., et al. (2010). Lipopolysaccharide-activated microglia induce dysfunction of the blood-brain barrier in rat microvascular endothelial cells co-cultured with microglia. Cell. Mol. Neurobiol. 30, 247-253. doi: 10.1007/s10571-009-9446-7
118. Szathmari, A., Champier, J., Ghersi-Egea, J. F., Jouvet, A., Watrin, C., Wierinckx, A., et al (2013). Molecular characterization of circumventricular organs and third ventricle ependyma in the rat: potential markers for periventricular tumors. Neuropathology 33, 17-29. doi: 10.1111/j.1440-1789.2012.01321.x
119. Tallquist, M. D., French, W. J., and Soriano, P. (2003). Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1:E52. doi: 10.1371/journal.pbio.0000052
120. Tam, S. J., Richmond, D. L., Kaminker, J. S., Modrusan, Z., Martin-McNulty, B., Cao, T. C., et al. (2012). Death receptors DR6 and TROY regulate brain vascular development. Dev. Cell 22, 403-417. doi: 10.1016/j.devcel.2011.11.018
121. Theis, M., Sohl, G., Eiberger, J., and Willecke, K. (2005). Emerging complexities in identity and function of glial connexins. Trends Neurosci. 28, 188-195. doi: 10.1016/j.tins.2005.02.006
122. Tietz, S., and Engelhardt, B. (2015). Brain barriers: crosstalk between complex tight junctions and adherens junctions. J. Cell Biol. 209, 493-506. doi: 10.1083/jcb.201412147
123. Trost, A., Lange, S., Schroedl, F., Bruckner, D., Motloch, A. K., Bogner, B., et al. (2016). Brain and retinal pericytes: origin, function and role. Front. Cell. Neurosci. 4:20. doi: 10.3389/fncel.2016.00020
124. Vallet, P. G., Charnay, Y., Boura, C., and Kiss, J. Z. (1991). Colocalization of delta sleep inducing peptide and luteinizing hormone releasing hormone in neurosecretory vesicles in rat median eminence. Neuroendocrinology 53, 103-106. doi: 10.1159/000125705
125. Velloso, L. A., and Schwartz, M. W. (2011). Altered hypothalamic function in diet-induced obesity. Int. J. Obes. 35, 1455-1465. doi: 10.1038/ijo.2011.56
126. Wagner, H. J., and Pilgrim, C. (1974). Extracellular and transcellular transport of horseradish peroxidase (HRP) through the hypothalamic tanycyte ependyma. Cell Tissue Res. 152, 477-491. doi: 10.1007/BF00218933
127. Wang, Y., Rattner, A., Zhou, Y., Williams, J., Smallwood, P. M., and Nathans, J. (2012). Norrin/Frizzled4 signaling in retinal vascular development and blood-brain barrier plasticity. Cell 151, 1332-1344. doi: 10.1016/j.cell.2012.10.042
128. Weindl, A., and Joynt, R. J. (1973). Barrier properties of the subcommissural organ. Arch. Neurol. 29, 16-22
129. Winkler, E. A., Bell, R., and Zlokovic, B. V. (2011). Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398-1405. doi: 10.1038/nn.2946
130. Woods, S. C., and Porte, D. Jr. (1977). Relationship between plasma and cerebrospinal fluid insulin levels of dogs. Am J. Physiol. 233, E331-E334
131. Wosik, K., Cayrol, R., Dodelet-Devillers, A., Berthelet, F., Bernard, M., Moumdjian, R., et al. (2007). Angiotensin II controls occludin function and is required for blood-brain barrier maintenance: relevance to multiple sclerosis. J. Neurosci. 27, 9032-9042. doi: 10.1523/JNEUROSCI.2088-07.2007
132. Xiao, G., and Gan, L. S. (2013). Receptor-mediated endocytosis and brain delivery of therapeutic biologics. Int. J. Cell Biol. 2013:703545. doi: 10.1155/2013/703545
133. Zenker, D., Begley, D., Bratzke, H., Rübsamen-Waigmann, H., and von Briesen, H. (2003). Human blood-derived macrophages enhance barrier function of cultured primary bovine and human brain capillary endothelial cells. J. Physiol. 551(Pt 3), 1023-1032. doi: 10.1113/jphysiol.2003.045880
134. Zhang, X., and van den Pol, N. A. (2016). Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis. Nat. Neurosci. 19, 1341-1347. doi: 10.1038/nn.4372
135. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J. M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425-432
136. Zhao, Z., Nelson, A. R., Betsholtz, C., and Zlokovic, B. V. (2015). Establishment and dysfunction of the blood-brain barrier. Cell 163, 1064-1078. doi: 10.1016/j.cell.2015.10.067
137. Zhou, Y., and Nathans, J. (2014). Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical Wnt signaling. Dev. Cell 31, 248-256. doi: 10.1016/j.devcel.2014.08.018
138. Zimmermann, K. W. (1923). Der feinere bau der blutcapillares. Z. Anat. Entwicklungsgesch. 68, 3-109. doi: 10.1007/978-3-642-92456-9
139. Zlokovic, B. V. (2008). The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178-201. doi: 10.1016/j.neuron.2008.01.003