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Licensed Unlicensed Requires Authentication Published by De Gruyter October 22, 2014

Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

Yaroslav Kolinko, Kristyna Krakorova, Jan Cendelin, Zbynek Tonar and Milena Kralickova


Brain microcirculation plays an important role in the pathogenesis of various brain diseases. Several specific features of the circulation in the brain and its functions deserve special attention. The brain is extremely sensitive to hypoxia, and brain edema is more dangerous than edema in other tissues. Brain vessels are part of the blood-brain barrier, which prevents the penetration of some of the substances in the blood into the brain tissue. Herein, we review the processes of angiogenesis and the changes that occur in the brain microcirculation in the most prevalent neurodegenerative diseases. There are no uniform vascular changes in the neurodegenerative diseases. In some cases, the vascular changes are secondary consequences of the pathological process, but they could also be involved in the pathogenesis of the primary disease and contribute to the degeneration of neurons, based on their quantitative characteristics. Additionally, we described the stereological methods that are most commonly used for generating qualitative and quantitative data to assess changes in the microvascular bed of the brain.

Corresponding author: Yaroslav Kolinko, Faculty of Medicine in Pilsen, Department of Histology and Embryology, Charles University in Prague, Karlovarská 48, 301 66 Pilsen, Czech Republic, e-mail: ; and Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Husova 3, 306 05 Pilsen, Czech Republic


This review was supported by project ED2.1.00/03.0076 from the European Regional Development Fund and the Charles University Research Fund (project number P36).

Competing interests: The authors declare that they have no competing interests.

Author contributions: The first two authors performed the literature search and wrote the manuscript. The last three authors contributed equally to the generating ideas, general editing, and commenting on the text. The final manuscript preparation was conducted by the first author. All authors read and approved the final manuscript.


Abbott, N.J., Rönnbäck, L., and Hansson, E. (2006). Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7, 41–53.10.1038/nrn1824Search in Google Scholar

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, 13–25.10.1016/j.nbd.2009.07.030Search in Google Scholar

Abernethy, W.B., Bell, M.A., Morris, M., and Moody, D.M. (1993). Microvascular density of the human paraventricular nucleus decreases with aging but not hypertension. Exp. Neurol. 121, 270–274.10.1006/exnr.1993.1095Search in Google Scholar

Adams, R.H., Wilkinson, G.A., Weiss, C., Diella, F., Gale, N.W., Deutsch, U., Risau, W., and Klein, R. (1999). Roles of ephrin B ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes. Dev. 13, 295–306.10.1101/gad.13.3.295Search in Google Scholar

Aird, W.C. (2007). Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ. Res. 100, 158–173.10.1161/01.RES.0000255691.76142.4aSearch in Google Scholar

Amenta, F., Ferrante, F., Mancini, M., Sabbatini, M., Vega, J.A., and Zaccheo, D. (1995). Effect of long-term treatment with the dihydropyridine-type calcium channel blocker darodipine (PY 108-068) on the cerebral capillary network in aged rats. Mech. Ageing Dev. 78, 27–37.10.1016/0047-6374(94)01513-LSearch in Google Scholar

Andrew, N., Pirbhai, A., Moffat, D., Rajapaksa, S., Wormald, P.J., Reid, M., and Selva, D. (2013). Mucus extravasation into the orbit during frontal sinus irrigation. Ophthal Plast Reconstr Surg. 29, 29–31.10.1097/IOP.0b013e3182622874Search in Google Scholar PubMed

Anwar, M., Weiss, J., and Weiss, H.R. (1992). Quantitative determination of morphometric indices of the total and perfused capillary network of the newborn pig brain. Pediatr. Res. 32, 542–546.10.1203/00006450-199211000-00010Search in Google Scholar PubMed

Arden, G.B. and Sivaprasad, S. (2012). The pathogenesis of early retinal changes of diabetic retinopathy. Doc. Ophthalmol. Adv. Ophthalmol. 124, 15–26.10.1007/s10633-011-9305-ySearch in Google Scholar PubMed

Armstrong, M.J., Litvan, I., Lang, A.E., Bak, T.H., Bhatia, K.P., Borroni, B., Boxer, A.L., Dickson, D.W., Grossman, M., Hallett, M., et al. (2013). Criteria for the diagnosis of corticobasal degeneration. Neurology 80, 496–503.10.1212/WNL.0b013e31827f0fd1Search in Google Scholar PubMed PubMed Central

Aumailley, M., Bruckner-Tuderman, L., Carter, W.G., Deutzmann, R., Edgar, D., Ekblom, P., Engel, J., Engvall, E., Hohenester, E., Jones, J.C., et al. (2005). A simplified laminin nomenclature. Matrix Biol. 24, 326–332.10.1016/j.matbio.2005.05.006Search in Google Scholar

Ausprunk, D.H. and Folkman, J. (1977). Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc. Res. 14, 53–65.10.1016/0026-2862(77)90141-8Search in Google Scholar

Baddeley, A.J., Gundersen, H.J., and Cruz-Orive, L.M. (1986). Estimation of surface area from vertical sections. J. Microsc. 142, 259–276.10.1111/j.1365-2818.1986.tb04282.xSearch in Google Scholar PubMed

Baruch, K. and Schwartz, M. (2013). CNS-specific T cells shape brain function via the choroid plexus. Brain Behav. Immun. 34, 11–16.10.1016/j.bbi.2013.04.002Search in Google Scholar PubMed

Bazzoni, G. and Dejana, E. (2004). Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol. Rev. 84, 869–901.10.1152/physrev.00035.2003Search in Google Scholar PubMed

Bell, R.D., Winkler, E.A., Sagare, A.P., Singh, I., LaRue, B., Deane, R., and Zlokovic, B.V. (2010). Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427.10.1016/j.neuron.2010.09.043Search in Google Scholar PubMed PubMed Central

Bonkowski, D., Katyshev, V., Balabanov, R.D., Borisov, A., and Dore-Duffy, P. (2011). The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS 8, 8.10.1186/2045-8118-8-8Search in Google Scholar PubMed PubMed Central

Borowsky, I.W. and Collins, R.C. (1989). Metabolic anatomy of brain: a comparison of regional capillary density, glucose metabolism, and enzyme activities. J. Comp. Neurol. 288, 401–413.10.1002/cne.902880304Search in Google Scholar PubMed

Bouras, C., Kövari, E., Herrmann, F.R., Rivara, C.B., Bailey, T.L., von Gunten, A., Hof, P.R., and Giannakopoulos, P. (2006). Stereologic analysis of microvascular morphology in the elderly: Alzheimer disease pathology and cognitive status. J. Neuropathol. Exp. Neurol. 65, 235–244.10.1097/01.jnen.0000203077.53080.2cSearch in Google Scholar PubMed

Boyce, R.W., Dorph-Petersen, K., Lyck, L., and Gundersen, H.J.G. (2010). Design-based stereology: introduction to basic concepts and practical approaches for estimation of cell number. Toxicol. Pathol. 38, 1011–1025.10.1177/0192623310385140Search in Google Scholar PubMed

Brændgaard, H. and Gundersen, H.J.G. (1986). The impact of recent stereological advances on quantitative studies of the nervous system. J. Neurosci. Methods 18, 39–78.10.1016/0165-0270(86)90112-3Search in Google Scholar

Brown, W.R. and Thore, C.R. (2011). Cerebral microvascular pathology in aging and neurodegeneration. Neuropathol. Appl. Neurobiol. 37, 56–74.10.1111/j.1365-2990.2010.01139.xSearch in Google Scholar

Brown, W.R., Moody, D.M., Thore, C.R., Challa, V.R., and Anstrom, J.A. (2007). Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well. J. Neurol. Sci. 257, 62–66.10.1016/j.jns.2007.01.015Search in Google Scholar

Buchweitz-Milton, E. and Weiss, H.R. (1987). Perfused capillary morphometry in the senescent brain. Neurobiol. Aging 8, 271–276.10.1016/0197-4580(87)90012-1Search in Google Scholar

Buée, L., Hof, P.R., Bouras, C., Delacourte, A., Perl, D.P., Morrison, J.H., and Fillit, H.M. (1994). Pathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathol. 87, 469–480.10.1007/BF00294173Search in Google Scholar

Burke, M., Zangenehpour, S., Mouton, P.R., and Ptito, M. (2009). Knowing what counts: unbiased stereology in the non-human primate brain. J. Vis. Exp. 14, 1–4.10.3791/1262Search in Google Scholar

Calhoun, M.E. and Mouton, P.R. (2001). Length measurement: new developments in neurostereology and 3D imagery. J. Chem. Neuroanat. 21, 257–265.10.1016/S0891-0618(01)00093-XSearch in Google Scholar

Caplan, B.A., Gerrity, R.G., and Schwartz, C.J. (1974). Endothelial cell morphology in focal areas of in vivo Evans blue uptake in the young pig aorta. I. Quantitative light microscopic findings. Exp. Mol. Pathol. 21, 102–117.10.1016/0014-4800(74)90082-3Search in Google Scholar

Carmeliet, P. (2005). Angiogenesis in life, disease and medicine. Nature 438, 932–936.10.1038/nature04478Search in Google Scholar PubMed

Carmeliet, P. and Jain, R.K. (2000). Angiogenesis in cancer and other diseases. Nature 407, 249–257.10.1038/35025220Search in Google Scholar PubMed

Carmeliet, P. and Jain, R.K. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307.10.1038/nature10144Search in Google Scholar PubMed PubMed Central

Cassot, F., Lauwers, F., Fouard, C., Prohaska, S., and Lauwers-Cances, V. (2006). A novel three-dimensional computer-assisted method for a quantitative study of microvascular networks of the human cerebral cortex. Microcirculation 13, 1–18.10.1080/10739680500383407Search in Google Scholar PubMed

Cavallaro, G., Filippi, L., Bagnoli, P., La Marca, G., Cristofori, G., Raffaeli, G., Padrini, L., Araimo, G., Fumagalli, M., Groppo, M., et al. (2014). The pathophysiology of retinopathy of prematurity: an update of previous and recent knowledge. Acta Ophthalmol. 92, 2–20.10.1111/aos.12049Search in Google Scholar PubMed

Cerdeira, A.S. and Karumanchi, S.A. (2012). Angiogenic factors in preeclampsia and related disorders. Cold Spring Harb. Perspect. Med. 2. pii: a006585. PMID: 23125198.Search in Google Scholar

Charidimou, A., Gang, Q., and Werring, D.J. (2012). Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and -clinical spectrum. J. Neurol. Neurosurg. Psychiatry 83, 124–137.10.1136/jnnp-2011-301308Search in Google Scholar PubMed

Chen, J.J., Salat, D.H., and Rosas, H.D. (2012). Complex relationships between cerebral blood flow and brain atrophy in early Huntington’s disease. Neuroimage 59, 1043–1051.10.1016/j.neuroimage.2011.08.112Search in Google Scholar PubMed PubMed Central

Chung, K.K., Anderson, N.E., Hutchinson, D., Synek, B., and Barber, P.A. (2011). Cerebral amyloid angiopathy related inflammation: three case reports and a review. J. Neurol. Neurosurg. Psychiatry 82, 20–26.10.1136/jnnp.2009.204180Search in Google Scholar PubMed

Cisbani, G., Freeman, T.B., Soulet, D., Saint-Pierre, M., Gagnon, D., Parent, M., Hauser, R.A., Barker, R.A., and Cicchetti, F. (2013). Striatal allografts in patients with Huntington’s disease: impact of diminished astrocytes and vascularization on graft viability. Brain 136, 433–443.10.1093/brain/aws359Search in Google Scholar PubMed

Claesson-Welsh, L. and Welsh, M. (2013). VEGFA and tumour angiogenesis. J. Intern. Med. 273, 114–127.10.1111/joim.12019Search in Google Scholar PubMed

Collinson, F.J., Seligmann, J., and Perren, T.J. (2012). Ovarian cancer: advances in first-line treatment strategies with a particular focus on anti-angiogenic agents. Curr. Oncol. Rep. 14, 509–518.10.1007/s11912-012-0274-4Search in Google Scholar PubMed

Critchley, M. (1929). Critical review: the nature and significance of senile plaques. J. Neurol. Psychopathol. 10, 124–139.10.1136/jnnp.s1-10.38.124Search in Google Scholar PubMed PubMed Central

Cucullo, L., Hossain, M., Puvenna, V., Marchi, N., and Janigro, D. (2011). The role of shear stress in blood-brain barrier endothelial physiology. BMC Neurosci. 12, 40.10.1186/1471-2202-12-40Search in Google Scholar

Dalkara, T., Gursoy-Ozdemir, Y., and Yemisci, M. (2011). Brain microvascular pericytes in health and disease. Acta Neuropathol. 122, 1–9.10.1007/s00401-011-0847-6Search in Google Scholar

Davis, H.R., Jr., Hoos, L.M., Tetzloff, G., Maguire, M., Zhu, L.J., Graziano, M.P., and Altmann, S.W. (2007). Deficiency of Niemann-Pick C1 Like 1 prevents atherosclerosis in ApoE-/- mice. Arterioscler. Thromb. Vasc. Biol. 27, 841–849.10.1161/01.ATV.0000257627.40486.46Search in Google Scholar

de la Torre, J.C. and Stefano, G.B. (2000). Evidence that Alzheimer’s disease is a microvascular disorder: the role of constitutive nitric oxide. Brain Res. Rev. 34, 119–136.10.1016/S0165-0173(00)00043-6Search in Google Scholar

de Lau, L.M. and Breteler, M.M. (2006). Epidemiology of Parkinson’s disease. Lancet Neurol. 5, 525–535.10.1016/S1474-4422(06)70471-9Search in Google Scholar

Deckel, A.W., Cohen, D., and Duckrow, R. (1998). Cerebral blood flow velocity decreases during cognitive stimulation in Huntington’s disease. Neurology 51, 1576–1583.10.1212/WNL.51.6.1576Search in Google Scholar PubMed

Dejana, E. (2004). Endothelial cell-cell junctions: happy together. Nat. Rev. Mol. Cell. Biol. 5, 261–270.10.1038/nrm1357Search in Google Scholar PubMed

DelleDonne, A., Klos, K.J., Fujishiro, H., Ahmed, Z., Parisi, J.E., Josephs, K.A., Frigerio, R., Burnett, M., Wszolek, Z.K., Uitti, R.J., et al. (2008). Incidental Lewy body disease and preclinical Parkinson disease. Arch. Neurol. 65, 1074–1080.10.1001/archneur.65.8.1074Search in Google Scholar PubMed

Demir, R., Yaba, A., and Huppertz, B. (2010). Vasculogenesis and angiogenesis in the endometrium during menstrual cycle and implantation. Acta Histochem. 112, 203–214.10.1016/j.acthis.2009.04.004Search in Google Scholar PubMed

Desai, B.S., Schneider, J.A., Li, J.L., Carvey, P.M., and Hendey, B. (2009). Evidence of angiogenic vessels in Alzheimer’s disease. J. Neural Transm. 116, 587–597.10.1007/s00702-009-0226-9Search in Google Scholar PubMed PubMed Central

Desai Bradaric, B., Patel, A., Schneider, J.A., Carvey, P.M., and Hendey, B. (2012). Evidence for angiogenesis in Parkinson’s disease, incidental Lewy body disease, and progressive supranuclear palsy. J. Neural. Transm. 119, 59–71.10.1007/s00702-011-0684-8Search in Google Scholar

Distler, J.H., Hirth, A., Kurowska-Stolarska, M., Gay, R.E., Gay, S., and Distler, O. (2003). Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q. J. Nucl. Med. 47, 149–161.Search in Google Scholar

Duran-Vilaregut, J., del Valle, J., Manich, G., Camins, A., Pallàs, M., Vilaplana, J., and Pelegrí, C. (2011). Role of matrix metalloproteinase-9 (MMP-9) in striatal blood-brain barrier disruption in a 3-nitropropionic acid model of Huntington’s disease. Neuropathol. Appl. Neurobiol. 37, 525–537.10.1111/j.1365-2990.2010.01157.xSearch in Google Scholar

Duvernoy, H., Delon, S., and Vannson, J.L. (1983). The vascularization of the human cerebellar cortex. Brain Res. Bull. 11, 419–480.10.1016/0361-9230(83)90116-8Search in Google Scholar

Emerich, D.F., Skinner, S.J., Borlongan, C.V., Vasconcellos, A.V., and Thanos, C.G. (2005). The choroid plexus in the rise, fall and repair of the brain. BioEssays 27, 262–274.10.1002/bies.20193Search in Google Scholar

Enomoto, K. and Okura, M. (2013). The total squared curvature of curves and approximation by piecewise circular curves. Results Math. 64, 215–228.10.1007/s00025-013-0310-1Search in Google Scholar

Eržen, I., Janáček, J., and Kubínová, L. (2011). Characterization of the capillary network in skeletal muscles from 3D data. Physiol. Res. 60, 1–13.10.33549/physiolres.931988Search in Google Scholar

Evans, M.C., Couch, Y., Sibson, N., and Turner, M.R. (2013). Inflammation and neurovascular changes in amyotrophic lateral sclerosis. Mol. Cell. Neurosci. 53, 34–41.10.1016/j.mcn.2012.10.008Search in Google Scholar

Fahn, S. (2003). Description of Parkinson’s disease as a clinical syndrome. Ann. N Y Acad. Sci. 991, 1–14.10.1111/j.1749-6632.2003.tb07458.xSearch in Google Scholar

Falcao, A.M., Marques, F., Novais, A., Sousa, N., Palha, J.A., and Sousa, J.C. (2012). The path from the choroid plexus to the subventricular zone: go with the flow! Front. Cell. Neurosci. 6, 34.10.3389/fncel.2012.00034Search in Google Scholar

Farkas, E. and Luiten, P.G. (2001). Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog. Neurobiol. 64, 575–611.10.1016/S0301-0082(00)00068-XSearch in Google Scholar

Farkas, E., de Vos, R.A., Donka, G., Jansen Steur, E.N., Mihály, A., and Luiten, P.G. (2006). Age-related microvascular degeneration in the human cerebral periventricular white matter. Acta Neuropathol. 111, 150–157.10.1007/s00401-005-0007-ySearch in Google Scholar PubMed

Fisher, M. (2009). Pericyte signaling in the neurovascular unit. Stroke 40, S13–S15.10.1161/STROKEAHA.108.533117Search in Google Scholar PubMed PubMed Central

Fleisher, A.S., Podraza, K.M., Bangen, K.J., Taylor, C., Sherzai, A., Sidhar, K., Liu, T.T., Dale, A.M., and Buxton, R.B. (2009). Cerebral perfusion and oxygenation differences in Alzheimer’s disease risk. Neurobiol. Aging 30, 1737–1748.10.1016/j.neurobiolaging.2008.01.012Search in Google Scholar PubMed PubMed Central

Fonseca, A.C., Ferreiro, E., Oliveira, C.R., Cardoso, S.M., and Pereira, C.F. (2013). Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochim. Biophys. Acta 1832, 2191–2203.10.1016/j.bbadis.2013.08.007Search in Google Scholar PubMed

Fox, S.B. and Harris, A.L. (2004). Histological quantitation of tumour angiogenesis. APMIS 112, 413–430.10.1111/j.1600-0463.2004.apm11207-0803.xSearch in Google Scholar PubMed

Franciosi, S., Ryu, J.K., Shim, Y., Hill, A., Connolly, C., Hayden, M.R., McLarnon, J.G., and Leavitt, B.R. (2012). Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease. Neurobiol. Dis. 45, 438–449.10.1016/j.nbd.2011.09.003Search in Google Scholar PubMed

Fraser, H.M. and Lunn, S.F. (2000). Angiogenesis and its control in the female reproductive system. Br. Med. Bull. 56, 787–797.10.1258/0007142001903364Search in Google Scholar PubMed

Freeman, T.B., Cicchetti, F., Bachoud-Lévi, A.C., and Dunnett, S.B. (2011). Technical factors that influence neural transplant safety in Huntington’s disease. Exp. Neurol. 227, 1–9.10.1016/j.expneurol.2010.08.031Search in Google Scholar PubMed

Gama Sosa, M.A., Gasperi, R.D., Rocher, A.B., Wang, A.C., Janssen, W.G., Flores, T., Perez, G.M., Schmeidler, J., Dickstein, D.L., Hof, P.R., et al. (2010). Age-related vascular pathology in transgenic mice expressing presenilin 1-associated familial Alzheimer’s disease mutations. Am. J. Pathol. 176, 353–368.10.2353/ajpath.2010.090482Search in Google Scholar PubMed PubMed Central

Garbuzova-Davis, S., Haller, E., Saporta, S., Kolomey, I., Nicosia, S.V., and Sanberg, P.R. (2007). Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res. 1157, 126–137.10.1016/j.brainres.2007.04.044Search in Google Scholar PubMed

Garbuzova-Davis, S., Rodrigues, M.C., Hernandez-Ontiveros, D.G., Louis, M.K., Willing, A.E., Borlongan, C.V., and Sanberg, P.R. (2011). Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res. 1398, 113–1125.10.1016/j.brainres.2011.04.049Search in Google Scholar PubMed

Garcia-Ovejero, D., Arevalo-Martin, A., Petrosino, S., Docagne, F., Hagen, C., Bisogno, T., Watanabe, M., Guaza, C., Di Marzo, V., and Molina-Holgado, E. (2009). The endocannabinoid system is modulated in response to spinal cord injury in rats. Neurobiol. Dis. 33, 57–71.10.1016/j.nbd.2008.09.015Search in Google Scholar PubMed

Geinisman, Y., Gunderson, H.J.G., Van Der Zee, E., and West, M.J. (1996). Unbiased stereological estimation of the total number of synapses in a brain region. J. Neurocytol. 12, 805–819.10.1007/BF02284843Search in Google Scholar PubMed

Ghebremedhin, E., Rosenberger, A., Rüb, U., Vuksic, M., Berhe, T., Bickeböller, H., de Vos, R.A., Thal, D.R., and Deller, T. (2010). Inverse relationship between cerebrovascular lesions and severity of Lewy body pathology in patients with Lewy body diseases. J. Neuropathol. Exp. Neurol. 69, 442–448.10.1097/NEN.0b013e3181d88e63Search in Google Scholar PubMed

Glaser, J., Greene, G., and Hendricks, S. (2007). Steriology for Biological Research With a Focus on Neuroscience (MBF Press, Williston, USA).Search in Google Scholar

Göbel, U., Theilen, H., and Kuschinsky, W. (1990). Congruence of total and perfused capillary network in rat brains. Circ. Res. 66, 271–281.10.1161/01.RES.66.2.271Search in Google Scholar

Greenberg, D.A. and Jin, K. (2005). From angiogenesis to neuropathology. Nature 438, 954–959.10.1038/nature04481Search in Google Scholar PubMed

Greenway, M.J., Andersen, P.M., Russ, C., Ennis, S., Cashman, S., Donaghy, C., Patterson, V., Swingler, R., Kieran, D., Prehn, J., et al. (2006). ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat. Genet. 38, 411–413.10.1038/ng1742Search in Google Scholar PubMed

Guan, J., Pavlovic, D., Dalkie, N., Waldvogel, H.J., O’Carroll, S.J., Green, C.R., and Nicholson, L.F. (2013). Vascular degeneration in Parkinson’s disease. Brain Pathol. 23, 154–164.10.1111/j.1750-3639.2012.00628.xSearch in Google Scholar PubMed PubMed Central

Gundersen, H.J. (1986). Stereology of arbitrary particles. A review of unbiased number and size estimators and the presentation of some new ones, in memory of William R. Thompson. J. Microsc. 143, 3–45.10.1111/j.1365-2818.1986.tb02764.xSearch in Google Scholar

Gundersen, H.J. and Jensen, E.B. (1987). The efficiency of systematic sampling in stereology and its prediction. J. Microsc. 147, 229–263.10.1111/j.1365-2818.1987.tb02837.xSearch in Google Scholar PubMed

Gundersen, H.J.G., Jensen, E.B.V., Kieu, K., and Nielsen, K. (1999). The efficiency of systematic sampling in stereology – reconsidered. J. Microsc. 193, 199–211.10.1046/j.1365-2818.1999.00457.xSearch in Google Scholar

Hamilton, N.B., Attwell, D., and Hall, C.N. (2010). Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front. Neuroenerg. 2. Published online.10.3389/fnene.2010.00005Search in Google Scholar

Hammarlund-Udenaes, M., Fridén, M., Syvänen, S., and Gupta, A. (2008). On the rate and extent of drug delivery to the brain. Pharm. Res. 25, 1737–1750.10.1007/s11095-007-9502-2Search in Google Scholar

Harb, R., Whiteus, C., Freitas, C., and Grutzendler, J. (2013). In vivo imaging of cerebral microvascular plasticity from birth to death. J. Cereb. Blood Flow Metab. 33, 146–156.10.1038/jcbfm.2012.152Search in Google Scholar

Hart, W.E., Goldbaum, M., Côté, B., Kube, P., and Nelson, M.R. (1997). Automated measurement of retinal vascular tortuosity. Proc. AMIA Annu. Fall Symp. 459–463. PMID 9357668.Search in Google Scholar

Hartmann, C., Zozulya, A., Wegener, J., and Galla, H.J. (2007). The impact of glia-derived extracellular matrices on the barrier function of cerebral endothelial cells: an in vitro study. Exp. Cell. Res. 313, 1318–1325.10.1016/j.yexcr.2007.01.024Search in Google Scholar

Hazzard, T.M. and Stouffer, R.L. (2000). Angiogenesis in ovarian follicular and luteal development. Baillières Best Pr. Res. Clin. Obstet. Gynaecol. 14, 883–900.Search in Google Scholar

Heinke, J., Patterson, C., and Moser, M. (2012). Life is a pattern: vascular assembly within the embryo. Front. Biosci. Elite Ed. 4, 2269–2288.10.2741/e541Search in Google Scholar

Heinzer, S., Kuhn, G., Krucker, T., Meyer, E., Ulmann-Schuler, A., Stampanoni, M., Gassmann, M., Marti, H.H., Müller, R., and Vogel, J. (2008). Novel three-dimensional analysis tool for vascular trees indicates complete micro-networks, not single capillaries, as the angiogenic endpoint in mice overexpressing human VEGF(165) in the brain. Neuroimage 39, 1549–1558.10.1016/j.neuroimage.2007.10.054Search in Google Scholar

Hicks, P., Rolsten, C., Brizzee, D., and Samorajski, T. (1983). Age-related changes in rat brain capillaries. Neurobiol. Aging 4, 69–75.10.1016/0197-4580(83)90057-XSearch in Google Scholar

Holthofer, H., Virtanen, I., and Kariniemi, A.L. (1982). Ulex europaeus I lectin as a marker for vascular endothelium in human tissues. Lab. Invest. 47, 60–66.Search in Google Scholar

Huang, C.X., Qiu, X., Wang, S., Wu, H., Xia, L., Li, C., Gao, Y., Zhang, L., Xiu, Y., Chao, F., et al. (2013). Exercise-induced changes of the capillaries in the cortex of differentiation in the rat retina in vivo. Invest. Ophthalmol. Vis. Sci. 45, 2795–2806.Search in Google Scholar

Hudetz, A.G. (1997). Blood flow in the cerebral capillary network—a review emphasizing observations with intravital microscopy. Microcirculation-London 4, 233–252.10.3109/10739689709146787Search in Google Scholar PubMed

Hughes, S., and Chan-Ling, T. (2004). Characterization of smooth muscle cell and pericyte differentiation in the rat retina in vivo. Invest. Ophthalmol. Vis. Sci. 45, 2795–2806.10.1167/iovs.03-1312Search in Google Scholar PubMed

Hunziker, O., Abdel’Al, S., and Schulz, U. (1979). The aging human cerebral cortex: a stereological characterization of changes in the capillary net. J. Gerontol. 34, 345–350.10.1093/geronj/34.3.345Search in Google Scholar

Iadecola, C. (2004). Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347–360.10.1038/nrn1387Search in Google Scholar

Iadecola, C. and Nedergaard, M. (2007). Glial regulation of the cerebral microvasculature. Nat. Neurosci. 10, 1369–1376.10.1038/nn2003Search in Google Scholar

Iglesias-Gamarra, A., Restrepo, J.F., and Matteson, E.L. (2007). Small-vessel vasculitis. Curr. Rheumatol. Rep. 9, 304–311.10.1007/s11926-007-0049-3Search in Google Scholar

Illsley, A. and Ramadan, H. (2014). Cerebral amyloid angiopathy: a transient ischaemic attack mimic. Clin. Med. 14, 255–259.10.7861/clinmedicine.14-3-255Search in Google Scholar

Jiménez, B., Volpert, O.V., Crawford, S.E., Febbraio, M., Silverstein, R.L., and Bouck, N. (2000). Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat. Med. 6, 41–48.10.1038/71517Search in Google Scholar

Johannessen, T.-C.A., Wagner, M., Straume, O., Bjerkvig, R., and Eikesdal, H.P. (2013). Tumor vasculature: the Achilles’ heel of cancer? Expert Opin. Ther. Targets 17, 7–20.10.1517/14728222.2013.730522Search in Google Scholar

Johanson, C.E., Stopa, E.G., and McMillan, P.N. (2011). The blood-cerebrospinal fluid barrier: structure and functional significance. Methods Mol. Biol. 686, 101–131.10.1007/978-1-60761-938-3_4Search in Google Scholar

Jucker, M., Bättig, K., and Meier-Ruge, W. (1990). Effects of aging and vincamine derivatives on pericapillary microenvironment: stereological characterization of the cerebral capillary network. Neurobiol. Aging 11, 39–46.10.1016/0197-4580(90)90060-DSearch in Google Scholar

Kalaitzakis, M.E., Graeber, M.B., Gentleman, S.M., and Pearce, R.K. (2008). Controversies over the staging of alpha-synuclein pathology in Parkinson’s disease. Acta Neuropathol. 116, 125–128.10.1007/s00401-008-0381-3Search in Google Scholar PubMed

Kalitzeos, A.A., Lip, G.Y., and Heitmar, R. (2013). Retinal vessel tortuosity measures and their applications. Exp. Eye Res. 106, 40–46.10.1016/j.exer.2012.10.015Search in Google Scholar PubMed

Kannurpatti, S.S., Motes, M.A., Rypma, B., and Biswal, B.B. (2010). Neural and vascular variability and the fMRI-BOLD response in normal aging. Magn. Reson. Imaging 28, 466–476.10.1016/j.mri.2009.12.007Search in Google Scholar PubMed PubMed Central

Karran, E., Mercken, M., and De Strooper, B. (2011). The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10, 698–712.10.1038/nrd3505Search in Google Scholar PubMed

Katsuse, O., Iseki, E., Arai, T., Akiyama, H., Togo, T., Uchikado, H., Kato, M., de Silva, R., Lees, A., and Kosaka, K. (2003). 4-repeat tauopathy sharing pathological and biochemical features of corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol. 106, 251–260.10.1007/s00401-003-0728-8Search in Google Scholar PubMed

Keuker, J.I., Luiten, P.G., and Fuchs, E. (2000). Capillary changes in hippocampal CA1 and CA3 areas of the aging rhesus monkey. Acta Neuropathol. 100, 665–672.10.1007/s004010000227Search in Google Scholar PubMed

Klein, T.W., Lane, B., Newton, C.A., and Friedman, H. (2000). The cannabinoid system and cytokine network. Proc. Soc. Exp. Biol. Med. 225, 1–8.10.1046/j.1525-1373.2000.22501.xSearch in Google Scholar PubMed

Kochová, P., Cimrman, R., Janáček, J., Witter, K., and Tonar, Z. (2011). How to asses, visualize and compare the anisotropy of linear structures reconstructed from optical sections – a study based on histopathological quantification of human brain microvessels. J. Theor. Biol. 286, 67–78.10.1016/j.jtbi.2011.07.004Search in Google Scholar PubMed

Konisti, S., Kiriakidis, S., and Paleolog, E.M. (2012). Hypoxia – a key regulator of angiogenesis and inflammation in rheumatoid arthritis. Nat. Rev. Rheumatol. 8, 153–162.10.1038/nrrheum.2011.205Search in Google Scholar PubMed

Krause, D.S., Fackler, M.J., Civin, C.I., and May, W.S. (1996). CD34: structure, biology, and clinical utility. Blood 87, 1–13.10.1182/blood.V87.1.1.1Search in Google Scholar

Krueger, M. and Bechmann, I. (2010). CNS pericytes: concepts, misconceptions, and a way out. Glia 58, 1–10.10.1002/glia.20898Search in Google Scholar PubMed

Kubínová, L., Mao, X.W., and Janáček, J. (2013). Blood capillary length estimation from three-dimensional microscopic data by image analysis and stereology. Microsc. Microanal. 19, 898–906.10.1017/S1431927613001487Search in Google Scholar PubMed

Kurozumi, K., Hardcastle, J., Thakur, R., Yangm, M., Christoforidis, G., Fulci, G., Hochberg, F.H., Weissleder, R., Carson, W., Chiocca, E.A., et al. (2007). Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy. J. Natl. Cancer Inst. 99, 1768–1781.10.1093/jnci/djm229Search in Google Scholar PubMed

Lee, G.D., Aruna, J.H., Barrett, P.M., Lei, D.L., Ingram, D.K., and Mouton, P.R. (2005). Stereological analysis of microvascular parameters in a double transgenic model of Alzheimer’s disease. Brain Res. Bull. 65, 317–322.10.1016/j.brainresbull.2004.11.024Search in Google Scholar PubMed

Li, C., Sun, C.J., Fan, J.C., Geng, N., Li, C.H., Liao, J., Mi, K., Zhu, G.Q., Ma, H., Song, et al. (2013a). Angiopoietin-2 expression is correlated with angiogenesis and overall survival in oral squamous cell carcinoma. Med. Oncol. 30, 571.10.1007/s12032-013-0571-2Search in Google Scholar PubMed

Li, Q., Lu, Q., Lu, H., Tian, S., and Lu, Q. (2013b). Systemic autoimmunity in TAM triple knockout mice causes inflammatory brain damage and cell death. PLoS One 8, e64812.10.1371/journal.pone.0064812Search in Google Scholar PubMed PubMed Central

Li, X., Wilder-Smith, C.H., Kan, M.E., Lu, J., Cao, Y., and Wong, R.K. (2014). Combat-training stress in soldiers increases S100B, a marker of increased blood-brain-barrier permeability, and induces immune activation. Neuro. Endocrinol. Lett. 35, 58–63.Search in Google Scholar

Lim, C.S., Kiriakidis, S., Sandison, A., Paleolog, E.M., and Davies, A.H. (2013). Hypoxia-inducible factor pathway and diseases of the vascular wall. J. Vasc. Surg. 58, 219–230.10.1016/j.jvs.2013.02.240Search in Google Scholar PubMed

Lin, W.L., Castanedes-Casey, M., and Dickson, D.W. (2009). Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease. J. Neuropathol. Exp. Neurol. 68, 1167–1176.10.1097/NEN.0b013e3181baacecSearch in Google Scholar PubMed PubMed Central

Lin, C.Y., Hsu, Y.H., Lin, M.H., Yang, T.H., Chen, H.M., Chen, Y.C., Hsiao, H.Y., Chen, C.C., Chern, Y., and Chang, C. (2013). Neurovascular abnormalities in humans and mice with Huntington’s disease. Exp. Neurol. 250, 20–30.10.1016/j.expneurol.2013.08.019Search in Google Scholar PubMed

Lipinski, B. and Pretorius, E. (2013). The role of iron-induced fibrin in the pathogenesis of Alzheimer’s disease and the protective role of magnesium. Front. Hum. Neurosci. 7, 735–746.10.3389/fnhum.2013.00735Search in Google Scholar PubMed PubMed Central

Liu, Z-J., Shirakawa, T., Li, Y., Soma, A., Oka, M., Dotto, G.P., Fairman, R.M., Velazquez, O.C., and Herlyn, M. (2003). Regulation of Notch1 and DLL4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol. Cell. Biol. 23, 14–25.10.1128/MCB.23.1.14-25.2003Search in Google Scholar PubMed PubMed Central

Løkkegaard, A., Nyengaard, J.R., and West, M.J. (2001). Stereological estimates of number and length of capillaries in subdivisions of the human hippocampal region. Hippocampus 11, 726–740.10.1002/hipo.1088Search in Google Scholar PubMed

Lokmic, Z. and Mitchell, G.M. (2011). Visualisation and stereological assessment of blood and lymphatic vessels. Histol. Histopathol. 26, 781–796.Search in Google Scholar

Love, S., Bridges, L.R., and Case, C.P. (1995). Neurofibrillary tangles in Niemann-Pick disease type C. Brain 118, 119–129.10.1093/brain/118.1.119Search in Google Scholar PubMed

Maat-Schieman, M.L., Dorsman, J.C., Smoor, M.A., Siesling, S., Van Duinen, S.G., Verschuuren, J.J., den Dunnen, J.T., Van Ommen, G.J., and Roos, R.A. (1999). Distribution of inclusions in neuronal nuclei and dystrophic neurites in Huntington disease brain. J. Neuropathol. Exp. Neurol. 58, 129–137.10.1097/00005072-199902000-00003Search in Google Scholar PubMed

MacDonald, N.J., Shivers, W.Y., Narum, D.L., Plum, S.M., Wingard, J.N., Fuhrmann, S.R., Liang, H., Holland-Linn, J., Chen, D.H., and Sim, B.K. (2001). Endostatin binds tropomyosin. A potential modulator of the antitumor activity of endostatin. J. Biol. Chem. 276, 25190–25196.10.1074/jbc.M100743200Search in Google Scholar PubMed

Makarov, N.S., Spiridonova, S.V., Nikitina, V.V., Voskresenskaia, O.N., and Zakharova, N.B. (2013). Molecular markers of endothelial damage in patients with Parkinson’s disease. Zh. Nevrol. Psikhiatr. Im S S Korsakova. 113, 61–64.Search in Google Scholar

Marques, F., Sousa, J.C., Sousa, N., and Palha, J.A. (2013). Blood-brain-barriers in aging and in Alzheimer’s disease. Mol. Neurodegener. 8, 38.10.1186/1750-1326-8-38Search in Google Scholar PubMed PubMed Central

Martínez-Jabaloyas, J.M., March-Villalba, J.A., Navarro-García, M.M., and Dasi, F. (2013). Anti-angiogenic therapies in prostate cancer. Expert Opin. Biol. Ther. 13, 1–5.10.1517/14712598.2013.733366Search in Google Scholar PubMed

Matej, R. and Rusina, R. (2012). Neurodegenerative disorders: review of current classification and diagnostic neuropathological criteria. Cesk. Patol. 48, 83–90.Search in Google Scholar

Mattfeldt, T., Mall, G., Gharehbaghi, H., and Möller, P. (1990). Estimation of surface area and length with the orientator. J. Microsc. 159, 301–317.10.1111/j.1365-2818.1990.tb03036.xSearch in Google Scholar PubMed

Mayeux, R. (2003). Epidemiology of neurodegeneration. Annu. Rev. Neurosci. 26, 81–104.10.1146/annurev.neuro.26.043002.094919Search in Google Scholar PubMed

Mayhew, M.J. (2005). Computer-aided bracket placement for indirect bonding. J. Clin. Orthod. 39, 653–660.Search in Google Scholar

Mayhew, T.M., Huppertz, B., Kaufmann, P., and Kingdom, J.C. (2003). The ‘reference trap’ revisited: examples of the dangers in using ratios to describe fetoplacental angiogenesis and trophoblast turnover. Placenta 24, 1–7.10.1053/plac.2002.0878Search in Google Scholar PubMed

Mazzetti, S., Frigerio, S., Gelati, M., Salmaggi, A., and Vitellaro-Zuccarello, L. (2004). Lycopersicon esculentum lectin: an effective and versatile endothelial marker of normal and tumoral blood vessels in the central nervous system. Eur. J. Histochem. 48, 423–428.10.4081/916Search in Google Scholar PubMed

McGovern, M.M., Pohl-Worgall, T., Deckelbaum, R.J., Simpson, W., Mendelson, D., Desnick, R.J., Schuchman, E.H., and Wasserstein, M.P. (2004). Lipid abnormalities in children with types A and B Niemann Pick disease. J. Pediatr. 145, 77–81.10.1016/j.jpeds.2004.02.048Search in Google Scholar

Miao, J., Xu, F., Davis, J., Otte-Höller, I., Verbeek, M.M., and Van Nostrand, W.E. (2005). Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am. J. Pathol. 167, 505–515.10.1016/S0002-9440(10)62993-8Search in Google Scholar

Miyazaki, K., Ohta, Y., Nagai, M., Morimoto, N., Kurata, T., Takehisa, Y., Ikeda, Y., Matsuura, T., and Abe, K. (2011). Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J. Neurosci. Res. 89, 718–728.10.1002/jnr.22594Search in Google Scholar PubMed

Montoya, A., Price, B.H., Menear, M., and Lepage, M. (2006). Brain imaging and cognitive dysfunctions in Huntington’s disease. J. Psychiatry Neurosci. 31, 21–29.Search in Google Scholar

Moreno, L., Popov, S., Jury, A., Al Sarraj, S., Jones, C., and Zacharoulis, S. (2013). Role of platelet derived growth factor receptor (PDGFR) over-expression and angiogenesis in ependymoma. J. Neurooncol. 111, 169–176.10.1007/s11060-012-0996-zSearch in Google Scholar PubMed

Mouton, P. (2011). Unbiased Stereology: A Concise Guide (Baltimore, MD: The Johns Hopkins University Press).Search in Google Scholar

Mouton, P.R., Gokhale, A.M., Ward, N.L., and West, M.J. (2002). Stereological length estimation using spherical probes. J. Microsc. 206, 54–64.10.1046/j.1365-2818.2002.01006.xSearch in Google Scholar PubMed

Muccioli, G.G. and Stella, N. (2008). Microglia produce and hydrolyze palmitoylethanolamide. Neuropharmacology 54, 16–22.10.1016/j.neuropharm.2007.05.015Search in Google Scholar PubMed PubMed Central

Mühlfeld, C., Schipke, J., Schmidt, A., Post, H., Pieske, B., and Sedej, S. (2013). Hypoinnervation is an early event in experimental myocardial remodelling induced by pressure overload. J. Anat. 222, 634–644.10.1111/joa.12044Search in Google Scholar PubMed PubMed Central

Nag, S. (2003). Morphological and molecular properties of cellular components of normal cerebral vessels. Methods Mol. Med. 89, 3–36.Search in Google Scholar

Nemoto, E.M. and Betterman, K. (2007). Basic physiology of hyperbaric oxygen in brain. Neurol. Res. 29, 116–126.10.1179/016164107X174138Search in Google Scholar PubMed

Newman, P.J. and Albelda, S.M. (1992). Cellular and molecular aspects of PECAM-1. Nouv. Rev. Fr. Hematol. 34, 9–13.Search in Google Scholar

Nicholson, C. (2001). Diffusion and related transport mechanisms in brain tissue. Rep. Prog. Phys. 64, 815–884.10.1088/0034-4885/64/7/202Search in Google Scholar

Novak, M.J., Warren, J.D., Henley, S.M., Draganski, B., Frackowiak, R.S., and Tabrizi, S.J. (2012). Altered brain mechanisms of emotion processing in pre-manifest Huntington’s disease. Brain 135, 1165–1179.10.1093/brain/aws024Search in Google Scholar PubMed PubMed Central

Nyengaard, J.R. and Gundersen, H.J.G. (1992). The isector: a simple and direct method for generating isotropic, uniform random sections from small specimens. J. Microsc. 165, 427–431.10.1111/j.1365-2818.1992.tb01497.xSearch in Google Scholar

Nyengaard, J.R. and Gundersen, H.J.G. (2006). Sampling for stereology in lungs. Eur. Respir. Rev. 15, 107–114.10.1183/09059180.00010101Search in Google Scholar

Oberheim, N.A., Takano, T., Han, X., He, W., Lin, J.H., Wang, F., Xu, Q., Wyatt, J.D., Pilcher, W., Ojemann, J.G., et al. (2009). Uniquely hominid features of adult human astrocytes. J. Neurosci. 29, 3276–3287.10.1523/JNEUROSCI.4707-08.2009Search in Google Scholar

Palop, J.J., Chin, J., and Mucke, L. (2006). A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768–773.10.1038/nature05289Search in Google Scholar

Pantoni, L. (2010). Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 9, 689–701.10.1016/S1474-4422(10)70104-6Search in Google Scholar

Patan, S., Alvarez, M.J., Schittny, J.C., and Burri, P.H. (1992). Intussusceptive microvascular growth: a common alternative to capillary sprouting. Arch. Histol. Cytol. 55, 65–75.10.1679/aohc.55.Suppl_65Search in Google Scholar PubMed

Peppiatt, C.M., Howarth, C., Mobbs, P., and Attwell, D. (2006). Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704.10.1038/nature05193Search in Google Scholar PubMed PubMed Central

Persidsky, Y., Ramirez, S.H., Haorah, J., and Kanmogne, G.D. (2006). Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J. Neuroimmune Pharmacol. 1, 223–236.10.1007/s11481-006-9025-3Search in Google Scholar PubMed

Peters, A. and Sethares, C. (2012). Age-related changes in the morphology of cerebral capillaries do not correlate with cognitive decline. J. Comp. Neurol. 520, 1339–1347.10.1002/cne.22809Search in Google Scholar PubMed

Pike, S.E., Yao, L., Jones, K.D., Cherney, B., Appella, E., Sakaguchi, K., Nakhasi, H., Teruya-Feldstein, J., Wirth, P., Gupta, G., et al. (1998). Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J. Exp. Med. 188, 2349–2356.10.1084/jem.188.12.2349Search in Google Scholar PubMed PubMed Central

Plate, K.H., Scholz, A., and Dumont, D.J. (2012). Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited. Acta Neuropathol. 124, 763–775.10.1007/s00401-012-1066-5Search in Google Scholar

Poewe, W. (2009). Treatments for Parkinson disease – past achievements and current clinical needs. Neurology 72, 65–73.10.1212/WNL.0b013e31819908ceSearch in Google Scholar

Price, J., Chi, X., Hellermann, G., and Sutton, E. (2001). Physiological levels of beta-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production. Neurol. Res. 23, 506–512.10.1179/016164101101198758Search in Google Scholar

Puchades, M., Sogn, C.J., Maehlen, J., Bergersen, L.H., and Gundersen, V. (2013). Unaltered lactate and glucose transporter levels in the MPTP mouse model of Parkinson’s disease. J. Parkinsons Dis. 3, 371–385.10.3233/JPD-130190Search in Google Scholar

Qiu, X., Li, C., Jiang, R., Chen, L., Huang, C., Yang, S., Lu, W., Shi, X., Zhao, Y., Gao, Y., et al. (2011). The effects of short-term enriched environment on capillaries of the middle-aged rat cortex. Neurosci. Lett. 505, 186–190.10.1016/j.neulet.2011.10.019Search in Google Scholar

Regan, R.F. and Guo, Y. (1998). Toxic effect of hemoglobin on spinal cord neurons in culture. J. Neurotrauma 15, 645–653.10.1089/neu.1998.15.645Search in Google Scholar

Reynolds, L.P., Grazul-Bilska, A.T., and Redmer, D.A. (2000). Angiogenesis in the corpus luteum. Endocrine 12, 1–9.10.1385/ENDO:12:1:1Search in Google Scholar

Reynolds, L.P., Grazul-Bilska, A.T., and Redmer, D.A. (2002). Angiogenesis in the female reproductive organs: pathological implications. Int. J. Exp. Pathol. 83, 151–163.10.1046/j.1365-2613.2002.00277.xSearch in Google Scholar

Riddle, D.R., Sonntag, W.E., and Lichtenwalner, R.J. (2003). Microvascular plasticity in aging. Ageing Res. Rev. 2i, 149–168.10.1016/S1568-1637(02)00064-8Search in Google Scholar

Risau, W. (1997). Mechanisms of angiogenesis. Nature 386, 671–674.10.1038/386671a0Search in Google Scholar

Robbins, S.L., Kumar, V., Abbas, A.K., Fausto, N., Aster J.C., Perkins, J.A. and Cotran, R.S. (2010). Pathologic Basis of Disease. 8th ed. (Saunders, an imprint of Elsevier Inc), China.Search in Google Scholar

Rossi, F., and Cattaneo, E. (2002). Neural stem cell therapy for neurological diseases: dreams and reality. Nat. Rev. Neurosci. 3, 401–409.10.1038/nrn809Search in Google Scholar

Sanes, J.R. (1989). Extracellular matrix molecules that influence neural development. Annu. Rev. Neurosci. 12, 491–516.10.1146/ in Google Scholar

Sarkar, S., Raymick, J., Mann, D., Bowyer, J.F., Hanig, J.P., Schmued, L.C., Paule, M.G., and Chigurupati, S. (2014). Neurovascular changes in acute, sub-acute and chronic mouse models of Parkinso’s disease. Curr. Neurovasc. Res. 11, 48–61.10.2174/1567202610666131124234506Search in Google Scholar

Sato. M., and Ohashi, T. (2005). Biorheological views of endothelial cell responses to mechanical stimuli. Biorheology. 42, 421–441.Search in Google Scholar

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, 742–752.10.1016/j.mam.2012.11.006Search in Google Scholar

Schouten, S.B., De Bruin, A.F., Gosselink, M.P., Nigg, A.L., van Iterson, M., Biermann, K., Kliffen, M., and van der Harst, E. (2014). Is microvessel density correlated with anastomotic leakage after low anterior resection? Hepatogastroenterology 61, 90–93.Search in Google Scholar

Schwartz, R.S., Halliday, G.M., Cordato, D.J., and Kril, J.J. (2012). Small-vessel disease in patients with Parkinso’’s disease: a clinicopathological study. Mov. Disord. 27, 1506–1512.10.1002/mds.25112Search in Google Scholar

Segal, M.B. (2001). Transport of nutrients across the choroid plexus. Microsc. Res. Tech. 52, 38–48.10.1002/1097-0029(20010101)52:1<38::AID-JEMT6>3.0.CO;2-JSearch in Google Scholar

Sengillo, J.D., Winkler, E.A., Walker, C.T., Sullivan, J.S., Johnson, M., and Zlokovic, B.V. (2013). Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheime’’s disease. Brain. Pathol. 23, 303–310.10.1111/bpa.12004Search in Google Scholar

Shao, W.H., Li, C., Chen, L., Qiu, X., Zhang, W., Huang, C.X., Xia, L., Kong, J.M., and Tang, Y. (2010). Stereological investigation of age-related changes of the capillaries in white matter. Anat. Rec. (Hoboken) 293, 1400–1407.10.1002/ar.21184Search in Google Scholar

Shepro, D. and Morel, N.M. (1993). Pericyte physiology. FASEB J. 7, 1031–1038.10.1096/fasebj.7.11.8370472Search in Google Scholar

Shibuya, K., Yagishita, S., Nakamura, A., and Uchihara, T. (2011). Perivascular orientation of astrocytic plaques and tuft-shaped astrocytes. Brain Res. 1404, 50–54.10.1016/j.brainres.2011.06.014Search in Google Scholar

Smith, C.S. and Guttman, L. (1953). Measurement of internal boundaries in three dimensional structures by random sectioning. Trans. AIME 197, 81–92.10.1007/BF03397456Search in Google Scholar

Sonntag, W.E., Lynch, C.D., Cooney, P.T., and Hutchins, P.M. (1997). Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1. Endocrinology. 138, 3515–3520.10.1210/endo.138.8.5330Search in Google Scholar

Staines, D.R., Brenu, E.W., and Marshall-Gradisnik, S. (2009). Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: a role for phosphodiesterase inhibitors in treatment? Neuropsychiatr. Dis. Treat. 5, 81–89.Search in Google Scholar

Steele, J.C., Richardson, J.C., and Olszewski, J. (1964). Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch. Neurol. 10, 333–359.10.1001/archneur.1964.00460160003001Search in Google Scholar

Stella, N. and Piomelli, D. (2001). Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur. J. Pharmacol. 425, 189–196.10.1016/S0014-2999(01)01182-7Search in Google Scholar

Sterio, D.C. (1984). The unbiased estimation of number and sizes of arbitrary particles using the disector. J. Microsc. 134, 127–136.10.1111/j.1365-2818.1984.tb02501.xSearch in Google Scholar PubMed

Streit, W.J., Mrak, R.E., and Griffin, W.S. (2004). Microglia and neuroinflammation: a pathological perspective. J. Neuroinflammation 1, 14.Search in Google Scholar

Su, M., Yoshida, Y., Hirata, Y., Satoh, Y., and Nagata, K. (2000). Degeneration of the cerebellar dentate nucleus in corticobasal degeneration: neuropathological and morphometric investigations. Acta Neuropathol. 99, 365–370.10.1007/s004010051137Search in Google Scholar PubMed

Su, X.W., Broach, J.R., Connor, J.R., Gerhard, G.S., and Simmons. Z. (2014). Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research. Muscle Nerve 49, 786–803.10.1002/mus.24198Search in Google Scholar PubMed

Sykova, E. and Nicholson, C. (2008). Diffusion in brain extracellular space. Physiol. Rev. 88, 1277–1340.10.1152/physrev.00027.2007Search in Google Scholar PubMed PubMed Central

Tahergorabi, Z. and Khazaei, M. (2012). A review on angiogenesis and its assays. Iran J. Basic Med. Sci. 15, 1110–1126.Search in Google Scholar

Takano, T., Tian, G.F., Peng, W., Lou, N., Libionka, W., Han, X., and Nedergaard, M. (2006). Astrocyte-mediated control of cerebral blood flow. Nat. Neurosci. 9, 260–267.10.1038/nn1623Search in Google Scholar PubMed

Taylor, P.C. and Sivakumar, B. (2005). Hypoxia and angiogenesis in rheumatoid arthritis. Curr. Opin. Rheumatol. 17, 293–298.10.1097/01.bor.0000155361.83990.5bSearch in Google Scholar PubMed

Tilling, T., Engelbertz, C., Decker, S., Korte, D., Hüwel, S., and Galla, H.J. (2002). Expression and adhesive properties of basement membrane proteins in cerebral capillary endothelial cell cultures. Cell. Tissue Res. 310, 19–29.10.1007/s00441-002-0604-1Search in Google Scholar

Tonar, Z., Kochová, P., Cimrman, R., Witter, K., Janáček, J., and Rohan, V. (2011). Microstructure oriented modelling of hierarchically perfused porous media for cerebral blood flow evaluation. Key Eng. Mater. 465, 286–289.10.4028/ in Google Scholar

Trickler, W.J., Lantz-McPeak, S.M., Robinson, B.L., Paule, M.G., Slikker, W., Jr., Biris, A.S., Schlager, J.J., Hussain, S.M., Kanungo, J., Gonzalez, C., et al. (2014). Porcine brain microvessel endothelial cells show pro-inflammatory response to the size and composition of metallic nanoparticles. Drug Metab. Rev. 46, 224–231.10.3109/03602532.2013.873450Search in Google Scholar

Tsunemi, S., Iwasaki, T., Kitano, S., Matsumoto, K., Takagi-Kimura, M., Kubo, S., Tamaoki, T., and Sano, H. (2013). Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis. Arthritis Res. Ther. 15, R75.10.1186/ar4252Search in Google Scholar

Vinters, H.V. (1987). Cerebral amyloid angiopathy. A critical review. Stroke 18, 311–324.Search in Google Scholar

Wang, L.N., Xu, D., Gui, Q.P., Zhu, M.W., Zhang, H.H., and Hu, Y.Z. (2004). Morphological and quantatitive capillary changes in aging human brain. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 26, 104–107.Search in Google Scholar

Wang, J.B., Wang, M.D., Li, E.X., and Dong, D.F. (2012). Advances and prospects of anginex as a promising anti-angiogenesis and anti-tumor agent. Peptides 38, 457–462.10.1016/j.peptides.2012.09.007Search in Google Scholar

Wang, X., Abraham, S., McKenzie, J.A., Jeffs, N., Swire, M., Tripathi, V.B., Luhmann, U.F., Lange, C.A., Zhai, Z., Arthur, H.M., et al. (2013). LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling. Nature 499, 306–311.10.1038/nature12345Search in Google Scholar

Weidner, N. (2008). Measuring intratumoral microvessel density. Methods Enzymol. 444, 305–323.10.1016/S0076-6879(08)02814-0Search in Google Scholar

West, M.J. (1999). Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci. 22, 51–61.10.1016/S0166-2236(98)01362-9Search in Google Scholar

West, M.J., Slomianka, L., and Gundersen, H.J.G. (1991). Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat. Rec. 231, 482–497.10.1002/ar.1092310411Search in Google Scholar PubMed

West, M.J., Kawas, C.H., Stewart, W.F., Rudow, G.L., and Troncoso, J.C. (2004). Hippocampal neurons in pre-clinical Alzheime’’s disease. Neurobiol. Aging 25, 1205–1212.10.1016/j.neurobiolaging.2003.12.005Search in Google Scholar PubMed

Winkler, E.A., Bell, R.D., and Zlokovic, B.V. (2011). Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398–1405.10.1038/nn.2946Search in Google Scholar PubMed PubMed Central

Winkler, E.A., Sengillo, J.D., Sullivan, J.S., Henkel, J.S., Appel, S.H., and Zlokovic, B.V. (2013). Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 125, 111–120.10.1007/s00401-012-1039-8Search in Google Scholar PubMed PubMed Central

Wong, A.D., Ye, M., Levy, A.F., Rothstein, J.D., Bergles, D.E., and Searson, P.C. (2013). The blood-brain barrier: an engineering perspective. Front. Neuroeng. 6, 7.10.3389/fneng.2013.00007Search in Google Scholar PubMed PubMed Central

Wurdinger, T. and Tannous, B.A. (2009). Glioma angiogenesis. Cell. Adhes. Migr. 3, 230–235.10.4161/cam.3.2.7910Search in Google Scholar PubMed PubMed Central

Yancopoulos, G.D., Davis, S., Gale, N.W., Rudge, J.S., Wiegand, S.J., and Holash, J. (2000). Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248.10.1038/35025215Search in Google Scholar PubMed

Zacchigna, S., Lambrechts, D., and Carmeliet, P. (2008). Neurovascular signalling defects in neurodegeneration. Nat. Rev. Neurosci. 9, 169–181.10.1038/nrn2336Search in Google Scholar PubMed

Zhang, Z., Yan, J., Chang, Y., ShiDu Yan, S., and Shi, H. (2011). Hypoxia inducible factor-1 as a target for neurodegenerative diseases. Curr. Med. Chem. 18, 4335–4343.10.2174/092986711797200426Search in Google Scholar PubMed PubMed Central

Zhong, Z., Deane, R., Ali, Z., Parisi, M., Shapovalov, Y., O’Banion, M.K., Stojanovic, K., Sagare, A., Boillee, S., Cleveland, D.W., et al. (2008). ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat. Neurosci. 11, 420–422.10.1038/nn2073Search in Google Scholar PubMed PubMed Central

Zhu, X.H., Qiao, H., Du, F., Xiong, Q., Liu, X., Zhang, X., Ugurbil, K., and Chen, W. (2012). Quantitative imaging of energy expenditure in human brain. Neuroimage 60, 2107–2117.10.1016/j.neuroimage.2012.02.013Search in Google Scholar PubMed PubMed Central

Zimmermann, D.R. and Dours-Zimmermann, M.T. (2008). Extracellular matrix of the central nervous system: from neglect to challenge. Histochem. Cell. Biol. 130, 635–653.10.1007/s00418-008-0485-9Search in Google Scholar PubMed

Zlokovic, B.V. (2008). The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201.10.1016/j.neuron.2008.01.003Search in Google Scholar

Zonta, M., Angulo, M.C., Gobbo, S., Rosengarten, B., Hossmann, K.A., Pozzan, T., and Carmignoto, G. (2003). Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat. Neurosci. 6, 43–50.10.1038/nn980Search in Google Scholar

Zygmunt, M., Herr, F., Münstedt, K., Lang, U., and Liang, O.D. (2003). Angiogenesis and vasculogenesis in pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol. 110, 10–18.10.1016/S0301-2115(03)00168-4Search in Google Scholar

Received: 2014-7-16
Accepted: 2014-9-25
Published Online: 2014-10-22
Published in Print: 2015-2-1

©2015 by De Gruyter

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