Abstract
In the current work, we conducted an immunocytochemical search for markers of ongoing neurogenesis (e.g. nestin) in auditory cortex from postmortem sections of autism spectrum disorder (ASD) and age-matched control donors. We found nestin labeling in cells of the vascular system, indicating blood vessels plasticity. Evidence of angiogenesis was seen throughout superior temporal cortex (primary auditory cortex), fusiform cortex (face recognition center), pons/midbrain and cerebellum in postmortem brains from ASD patients but not control brains. We found significant increases in both nestin and CD34, which are markers of angiogenesis localized to pericyte cells and endothelial cells, respectively. This labeling profile is indicative of splitting (intussusceptive), rather than sprouting, angiogenesis indicating the blood vessels are in constant flux rather than continually expanding.
Similar content being viewed by others
References
Akbari, H. M., Whitaker-Azmitia, P. M., & Azmitia, E. C. (1994). Prenatal cocaine decreases the trophic factor S-100beta and induced microcephaly: Reversal by postnatal 5-HT1A receptor agonist. Neuroscience Letters, 170(1), 141–144.
Anderson, G. M. (2002). Genetics of childhood disorders: XLV. Autism, part 4: Serotonin in autism. Journal of American Academy of Child. Adolescent Psychiatry, 41(12), 1513–1516.
Azmitia, E. C., & Impallomeni, A. (2014). Dynamic brain changes in autism: review of telencephalic structures. In Comprehensive guide to autism (pp 695–716).
Azmitia, E. C., & Nixon, R. (2008). Dystrophic serotonergic axons in neurodegenerative diseases. Brain Research, 27(1217), 185–194.
Azmitia, E. C., Singh, J. S., Hou, X. P., & Wegiel, J. (2011a). Dystrophic serotonin axons in postmortem brains from young autism patients. Anatomical Record, 294, 1653–1662.
Azmitia, E. C., Singh, J. S., Whitaker-Azmitia, P. M., et al. (2011b). Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharmacology, 60, 1347–1354.
Bandopadhyay, R., Orte, C., Lawrenson, J. G., Reid, A. R., De Silva, S., & Allt, G. (2001). Contractile proteins in pericytes at the blood-brain and blood-retinal barriers. Journal of Neurocytology, 30(1), 35–44.
Bigler, E. D., Mortensen, S., Neeley, E. S., Ozonoff, S., Krasny, L., Johnson, M., et al. (2007). Superior temporal gyrus, language function, and autism. Developmental Neuropsychology, 31(2), 217–238.
Blatt, G. J. (2012). The neuropathology of autism. Scientifica (Cairo), 2012(2012), 703675.
Boddaert, N., Zilbovicius, M., Philipe, A., Robel, L., Bourgeois, M., Barthélemy, C., et al. (2009). MRI findings in 77 children with non-syndromic autistic disorder. PLoS ONE, 4(2), e4415.
Boldrini, M., Hen, R., Underwood, M. D., Rosoklija, G. B., Dwork, A. J., Mann, J. J., et al. (2012). Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biological Psychiatry, 72(7), 562–571.
Burri, P. H., Djonov, V. G., & Kurz, H. (2002). Optimality in the developing vascular system: Branching remodeling by means of intussusception as an efficient adaptation mechanism. Developmental Dynamics, 224(4), 391–402.
Casanova, M. F., van Kooten, I. A., Switala, A. E., van Engeland, H., Heinsen, H., Steinbusch, H. W., et al. (2006). Minicolumnar abnormalities in autism. Acta Neuropathologica, 112(3), 287–303.
Casanova, M. F., El-Baz, A., Mott, M., Mannheim, G., Hassan, H., Fahmi, R., et al. (2009). Reduced gyral window and corpus callosum size in autism: Possible macroscopic correlates of a minicolumnopathy. Journal of Autism and Developmental Disorders, 39(5), 751–764.
Casanova, M. F., El-Baz, A. S., Kamat, S. S., Dombroski, B. A., Khalifa, F., Elnakib, A., et al. (2013). Focal cortical dysplasias in autism spectrum disorders. Acta Neuropathologica Communications, 1(1), 67.
Courchesne, E. (1997). Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Current Opinion in Neurobiology, 7(2), 269–278.
Courchesne, E., Mouton, P. R., Calhoun, M. E., Semendeferi, K., Ahrens-Barbeau, C., Hallet, M. J., et al. (2011). Neuron number and size in prefrontal cortex of children with autism. Journal of the American Medical Association, 306(18), 2001–2010.
Covas, D. T., Panepucci, R. A., Fontes, A. M., Silva, W. A., Orellana, M. D., Freitas, M. C., et al. (2008). Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146 + perivascular cells and fibroblasts. Experimental Hematology, 36, 642–654.
De Spiegelaere, W., Cornillie, P., Van den Broeck, W., Plendl, J., & Bahramsoltani, M. (2011). Angiopoietins differentially influence in vitro angiogenesis by endothelial cells of different origin. Clinical Hemorheology Microcirculation, 48, 15–27.
Djonov, V. G., Kurz, H., & Burri, P. H. (2002). Optimality in the developing vascular system: In branching remodeling by means of intussusception as an efficient adaptation mechanism. Developmental Dynamics, 224(4), 391–402.
Dore-Duffy, P., Katychev, A., Van Buren, E., & Wang, X. (2006). CNS microvascular pericytes exhibit multipotential stem cell activity. Journal of Cerebral Blood Flow and Metabolism, 26, 613–624.
Dore-Duffy, P., Bradley, M., Gow, A., Mehedi, A., Trotter, R., & Wang, X. (2011). Immortalized CNS pericytes are quiescent smooth muscle actin-negative and pluripotent. Microvascular Research, 82(1), 18–27.
Dzietko, M., Derugin, N., Ferriero, D. M., Wendland, M. F., & Vexler, Z. S. (2013). Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Translational Stroke Research, 4, 189–200.
Farahani, R. M., Sarrafpour, B., Simonian, M., Li, Q., & Hunter, N. (2012). Directed glia-assisted angiogenesis in a mature neurosensory structure: Pericytes mediate an adaptive response in human dental pulp that maintains blood-barrier function. Journal of Comparative Neurology, 520(17), 3803–3826.
Fatemi, S. H., Earle, J., Halt, A. R., Kirst, D. A., Merz, A., Realmuto, G., et al. (2002). Purkinje cell size is reduced in cerebellum of patients with autism. Cell Molecular Neurobiology, 22(2), 171–175.
Fatemi, S. H., Reutiman, T. J., Folsom, T. D., Rustan, O. G., Rooney, R. J., & Thuras, P. D. (2014). Downregulation of GABAA receptor protein subunits α6, β2, δ, ε, γ2, θ, and ρ2 in superior frontal cortex of subjects with autism. Journal of Autism and Developmental Disorders, 44(8), 1833–1845.
Fraser, R. A., Ellis, E. M., & Stalker, A. L. (1979). Experimental angiogenesis in the chorio-allantoic membrane. Bibliotheca Anatomia, 18, 25–27.
Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., & Hardan, A. Y. (2014). Brief report: An open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Journal of Autism and Developmental Disorders, 44(11), 2971–2977.
Gerlach, J. C., Over, P., Turner, M. E., Thompson, R. L., Foka, H. G., Chen, W. C., et al. (2012). Perivascular mesenchymal progenitors in human fetal and adult liver. Stem Cells and Development, 21(18), 3258–3269.
Goligorsky, M. S., & Salven, P. (2013). Concise review: Endothelial Stem and progenitor cells and their habitats. Stem Cells Translational Medicine, 2(7), 499–504.
Guy, J., Perreault, A., Mottron, L., & Bertone, A. (2015). A systematic examination of early perceptual influences on low-, mid and high-level visual abilities in autism spectrum disorder. Journal of Vision, 15(12), 644. doi:10.1167/15.12.644.
Haar, S., Berman, S., Behrmann, M., & Dinstein, I. (2014). Anatomical abnormalities in autism? Cerebral Cortex, 1–13.
Hellendoorn, A., Wijnroks, L., van Daalen, E., Dietz, C., Buitelaar, J. K., & Leseman, P. (2015). Motor functioning, exploration, visuospatial cognition and language development in preschool children with autism. Research in Developmental Disabilities, 39, 32–42.
Hirschi, K. K., & D’Amore, P. A. (1997). Control of angiogenesis by the pericyte: Molecular mechanisms and significance. Experientia Supplementum, 79, 419–428.
Holthöfer, H., Virtanen, I., Kariniemi, A. L., Hormia, M., Linder, E., & Miettinen, A. (1982). Ulex europaeus I lectin as a marker for vascular endothelium in human tissues. Laboratory Investigation, 47(1), 60–66.
Hughes, J. R., & Melyn, M. (2005). EEG and seizures in autistic children and adolescents: Further findings with therapeutic implications. Clinical EEG and Neuroscience, 36(1), 15–20.
Hutsler, J. J., & Casanova, M. F. (2015). Cortical construction in autism spectrum disorder: columns, connectivity and the subplate. Neuropathololgy and Applied Neurobiology (in press).
Jacot-Descombes, S., Uppal, N., Wicinski, B., Santos, M., Schmeidler, J., Giannakopoulos, P., et al. (2012). Decreased pyramidal neuron size in Brodmann areas 44 and 45 in patients with autism. Acta Neuropathologica, 124(1), 67–79.
Jones, K. B., Cottle, K., Bakian, A., Farley, M., Bilder, D., Coon, H., et al. (2015). A description of medical conditions in adults with autism spectrum disorder: A follow-up of the 1980 s Utah/UCLA Autism Epidemiologic Study. Autism (in press).
Kennedy, D. P., Redcay, E., & Courchesne, E. (2006a). Failing to deactivate: Resting functional abnormalities in autism. Proceedings of the National Academy of Sciences of the United States America, 103(21), 8275–8280.
Kennedy, D. P., Redcay, E., & Courchesne, E. (2006b). Failing to deactivate: Resting functional abnormalities in autism. Proceedings of the National Academy of Sciences of the United States America, 103(21), 8275–8280.
Keown, C. L., Shih, P., Nair, A., Peterson, N., Mulvey, M. E., & Müller, R. A. (2013). Local functional overconnectivity in posterior brain regions is associated with symptom severity in autism spectrum disorders. Cell Reports, 5(3), 567–572.
Kulesza Jr., R. J., Lukose, R., & Stevens, L. V. (2011). Malformation of the human superior olive in autistic spectrum disorders. Brain Research, 1367:360–371. (significant decrease in the number of SOC neurons in the autistic brain).
Kurth, F., Narr, K. L., Woods, R. P., O’Neill, J., Alger, J. R., Caplan, R., et al. (2011). Diminished gray matter within the hypothalamus in autism disorder: A potential link to hormonal effects? Biology Psychiatry, 70(3), 278–282.
Lam, K. S., Aman, M. G., & Arnold, L. E. (2006). Neurochemical correlates of autistic disorder: A review of the literature. Research on Developmental Disabilities, 27(3), 254–289.
Lendahl, U., Zimmerman, L. B., & McKay, R. D. (1990). CNS stem cells express a new class of intermediate filament protein. Cell, 60(4), 585–595.
Leyfer, O. T., Folstein, S. E., Bacalman, S., Davis, N. O., Dinh, E., Morgan, J., et al. (2006). Comorbid psychiatric disorders in children with autism: Interview development and rates of disorders. Journal of Autism and Developmental Disorders, 36(7), 849–861.
Maenner, M. J., Arneson, C. L., Levy, S. E., Kirby, R. S., Nicholas, J. S., Durkin, M. S., et al. (2012). Brief report: Association between behavioral features and gastrointestinal problems among children with autism spectrum disorder. Journal of Autism and Developmental Disorders, 42(7), 1520–1525.
Marchi, N., & Lerner-Natoli, M. (2013). Cerebrovascular remodeling and epilepsy. Neuroscientist, 19(3), 304–312.
Marcon, J., Gagliardi, B., Balosso, S., Maroso, M., Noe, F., Morin, M., et al. (2009). Age-dependent vascular changes induced by status epilepticus in rat forebrain: Implications for epileptogenesis. Neurobiology of Disease, 34(1), 121–132.
Michalczyk, K., & Ziman, M. (2005). Nestin structure and predicted function in cellular cytoskeletal organization. Histology and Histopathology, 20(2), 665–671.
Morin-Brureau, M., Rigau, V., & Lerner-Natoli, M. (2012). Why and how to target angiogenesis in focal epilepsies. Epilepsia, 53(Supplement s6), 64–68.
Mulligan, C. K., & Trauner, D. A. (2014). Incidence and behavioral correlates of epileptiform abnormalities in autism spectrum disorders. Journal of Autism and Developmental Disorders, 44, 452–458.
O’Connor, K., & Kirk, I. (2008). Brief report: atypical social cognition and social behaviours in autism spectrum disorder: A different way of processing rather than an impairment. Journal of Autism and Developmental Disorders, 38(10), 1989–1997.
Ozen, S., Darcan, S., Bayindir, P., Karasulu, E., Simsek, D. G., & Gurler, T. (2012). Effects of pesticides used in agriculture on the development of precocious puberty. Environmental Monitoring and Assessment, 184(7), 4223–4232.
Peichev, M., Naiyer, A. J., Pereira, D., Zhu, Z., Lane, W. J., Williams, M., et al. (2000). Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood, 95(3), 952–958.
Perez Velazquez, J. L., Barcelo, F., Hung, Y., Leshchenko, Y., Nenadovic, V., Belkas, J., et al. (2009). Decreased brain coordinated activity in autism spectrum disorders during executive tasks: Reduced long-range synchronization in the fronto-parietal networks. International Journal of Psychophysiology, 73(3), 341–349.
Peters, M. A., Walenkamp, A. M., Kema, I. P., Meijer, C., de Vries, E. G., & Oosting, S. F. (2014). Dopamine and serotonin regulate tumor behavior by affecting angiogenesis. Drug Resistance Updates, 17(4–6), 96–104.
Poole, D., Gowen, E., Warren, P. A., & Poliakoff, E. (2015). Investigating visual–tactile interactions over time and space in adults with autism. Journal of Autism and Developmental Disorders, 45(10), 3316–3326.
Rigau, V., Morin, M., Rousset, M. C., de Bock, F., Lebrun, A., Coubes, P., et al. (2007). Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain, 130(7), 1942–1956.
Rodier, P. M., Ingram, J. L., Tisdale, B., Nelson, S., & Romano, J. (1996). Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. Journal of Comparative Neurology, 370(2), 247–261.
Romariz, S. A., Garcia, K. de O., Paiva, D. de S., Bittencourt, S., Covolan, L., Mello, L. E., et al. (2014). Articipation of bone marrow-derived cells in hippocampal vascularization after status epilepticus. Seizure, 23, 386-389.
Rumsey, J. M., & Ernst, M. (2000). Functional neuroimaging of autistic disorders. Mental Retardation and Developmental Disabilities Research Reviews, 6(3), 171–179.
Rumsey, J. M., Duara, R., Grady, C., Rapoport, J. L., Margolin, R. A., Rapoport, S. I., et al. (1985). Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography. Archives of General Psychiatry, 42(5), 448–455.
Sakurai, M., Morita, T., Takeuchi, T., & Shimada, A. (2013). Relationship of angiogenesis and microglial activation to seizure-induced neuronal death in the cerebral cortex of Shetland Sheepdogs with familial epilepsy. American Journal of Veterinary Research, 74(5), 763–770.
Seal, B. C., & Bonvillian, J. D. (1997). Sign language and motor functioning in students with autistic disorder. Journal of Autism and Developmental Disorders, 27(4), 437–466.
Siegel, B. V, Jr, Asarnow, R., Tanguay, P., Call, J. D., Abel, L., Ho, A., et al. (1992). Regional cerebral glucose metabolism and attention in adults with a history of childhood autism. Journal of Neuropsychiatry and Clinical Neurosciences, 4(4), 406–414.
Simonoff, E., Pickles, A., Charman, T., Chandler, S., Loucas, T., & Baird, G. (2008). Psychiatric disorders in children with autism spectrum disorders: Prevalence, comorbidity, and associated factors in a population-derived sample. Journal of American Academy of Child & Adolescent Psychiatry, 47(8), 921–929.
Stiegler, L., & Davis, R. (2010). Understanding sound sensitivity in individuals with autism spectrum disorders. Focus on Autism and Other Developmental, 20(10), 1–9.
Supekar, K., Uddin, L. Q., Khouzam, A., Phillips, J., Gaillard, W. D., Kenworthy, L. E., et al. (2013). Brain hyperconnectivity in children with autism and its links to social deficits. Cell Reports, 5(3), 738–747.
Thabet, E. M. (2014). Ocular vestibular evoked myogenic potentials n10 response in autism spectrum disorders children with auditory hypersensitivity: An indicator of semicircular canal dehiscence. European Archives of Oto-Rhino-Laryngology, 271(5), 1283–1288.
Thanabalasundaram, G., Arumalla, N., Tailor, H. D., & Khan, W. S. (2011). Regulation of differentiation of mesenchymal stem cells into musculoskeletal cells. Current Stem Cell Research Therapy, 7(2), 95–102.
Toribatake, Y., Tomita, K., Kawahara, N., Baba, H., Ohnari, H., & Tanaka, S. (1997). Regulation of vasomotion of arterioles and capillaries in the cat spinal cord: Role of alpha actin and endothelin-1. Spinal Cord, 35(1), 26–32.
Tuchman, R. (2013). Autism and social cognition in epilepsy: Implications for comprehensive epilepsy care. Current Opinion in Neurology, 26, 214–218.
Uppal, N., Wicinski, B., Buxbaum, J. D., Heinsen, H., Schmitz, C., & Hof, P. R. (2014). Neuropathology of the anterior midcingulate cortex in young children with autism. Journal of Neuropathology and Experimental Neurology, 73(9), 891–902.
Valvo, G., Baldini, S., Retico, A., Rossi, G., Tancredi, R., Ferrari, A.R., et al. (2015). Temporal lobe connects regression and macrocephaly to autism spectrum disorders. European Child and Adolescent Psychiatry (in press).
Van Kooten, I. A., Palmen, S. J., von Cappeln, P., Steinbusch, H. W., Korr, H., Heinsenm, H., et al. (2008). Neurons in the fusiform gyrus are fewer and smaller in autism. Brain, 131(4), 987–999.
Ventola, P. E., Oosting, D., Anderson, L. C., & Pelphrey, K. A. (2013). Brain mechanisms of plasticity in response to treatments for core deficits in autism. Progress in Brain Research, 207, 255–272.
Warner-Schmidt, J. L., & Duman, R. S. (2007). VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proceedings of the National Academy of Science USA, 104(11), 4647–4652.
Wegiel, J., Kuchna, I., Nowicki, K., Imaki, H., Wegiel, J., Marchi, E., et al. (2010). The neuropathology of autism: Defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathologica, 119(6), 755–770.
Wegiel, J., Kuchna, I., Nowicki, K., Imaki, H., Wegiel, J., Ma, S. Y., et al. (2013). Contribution of olivofloccular circuitry developmental defects to atypical gaze in autism. Brain Research, 28(1512), 106–122.
Whitaker-Azmitia, P. M. (2005). Behavioral and cellular consequences of increasing serotonergic activity during brain development: A role in autism? International Journal of Developmental Neuroscience, 23(1), 75–83.
Whyte, E., Elbich, D., Behrmann, M., Minshew, N., & Scherf, K. S. (2015). Altered functional connectivity in the core and extended face-processing network in adolescents with autism. Journal of Vision, 15(12), 1209.
Xiao, Z., Qiu, T., Ke, X., Xiao, X., Xiao, T., Liang, F., et al. (2014). Autism spectrum disorder as early neurodevelopmental disorder: Evidence from the brain imaging abnormalities in 2–3 years old toddlers. Journal of Autism and Developmental Disorders, 44(7), 1633–1640.
Zengin, E., Chalajour, F., Gehling, U. M., Ito, W. D., Treede, H., Lauke, H., et al. (2006). Vascular wall resident progenitor cells: A source for postnatal vasculogenesis. Development, 133(8), 1543–1551.
Zhang, Z. G., Zhang, L., Tsang, W., Soltanian-Zadeh, H., Morris, D., Zhang, R., et al. (2002). Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. Journal Cerebral Blood Flow and Metabolism, 22, 379–392.
Acknowledgments
NYU Challenge Grant 2014–2015 (Azmitia) and NIMH R01MH083862-05 (Boldrini) provided the necessary support for this work. Dr. Jerzy Wegiel for his invaluable advice and support during this work and also for contributing human postmortem tissue. Dr. Jane Pickett for her encouragement throughout this project and her help in obtaining postmortem tissue from the Autism Tissue Program. Dr. H.R. Zielke for providing postmortem brain tissue from the NICHD brain bank and, in particular, for making available samples from a autism donor who died from serotonin syndrome. Finally, helpful technical work was supplied by Victoria Lee, Amritpal Saini, Hanna Chen, Pooja P Kothari and Gordon Jiang.
Author Contributions
EA participated in all aspects of the study from concept to drafting the manuscript; ZS coordination of the study and performed the measurement; participated in the design and interpretation of the data; performed the statistical analysis; helped to draft the manuscript; MA coordination of the study and performed the measurement; helped to draft the manuscript; MB participated in the design of the study and performed the statistical analysis; PW participated in the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Azmitia, E.C., Saccomano, Z.T., Alzoobaee, M.F. et al. Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum. J Autism Dev Disord 46, 1307–1318 (2016). https://doi.org/10.1007/s10803-015-2672-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10803-015-2672-6