title: Brain angioarchitecture and intussusceptive microvascular growth in a murine model of Krabbe disease.
abstract: Defects of the angiogenic process occur in the brain of twitcher mouse, an authentic model of human Krabbe disease caused by genetic deficiency of lysosomal β-galactosylceramidase (GALC), leading to lethal neurological dysfunctions and accumulation of neurotoxic psychosine in the central nervous system. Here, quantitative computational analysis was used to explore the alterations of brain angioarchitecture in twitcher mice. To this aim, customized ImageJ routines were used to assess calibers, amounts, lengths and spatial dispersion of CD31(+) vessels in 3D volumes from the postnatal frontal cortex of twitcher animals. The results showed a decrease in CD31 immunoreactivity in twitcher brain with a marked reduction in total vessel lengths coupled with increased vessel fragmentation. No significant changes were instead observed for the spatial dispersion of brain vessels throughout volumes or in vascular calibers. Notably, no CD31(+) vessel changes were detected in twitcher kidneys in which psychosine accumulates at very low levels, thus confirming the specificity of the effect. Microvascular corrosion casting followed by scanning electron microscopy morphometry confirmed the presence of significant alterations of the functional angioarchitecture of the brain cortex of twitcher mice with reduction in microvascular density, vascular branch remodeling and intussusceptive angiogenesis. Intussusceptive microvascular growth, confirmed by histological analysis, was paralleled by alterations of the expression of intussusception-related genes in twitcher brain. Our data support the hypothesis that a marked decrease in vascular development concurs to the onset of neuropathological lesions in twitcher brain and suggest that neuroinflammation-driven intussusceptive responses may represent an attempt to compensate impaired sprouting angiogenesis.
authors: Unit of Experimental Oncology and Immunology, University of Brescia, Brescia, Italy.
authors: Arianna
authors: A
authors: Giacomini
authors: Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors: Maximilian
authors: M
authors: Ackermann
authors: Unit of Experimental Oncology and Immunology, University of Brescia, Brescia, Italy.
authors: Mirella
authors: M
authors: Belleri
authors: Unit of Histology, Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123, Brescia, Italy.
authors: Daniela
authors: D
authors: Coltrini
authors: Unit of Human Anatomy and Histology, Department of Basic Biomedical Sciences, University of Bari, Bari, Italy.
authors: Beatrice
authors: B
authors: Nico
authors: Unit of Human Anatomy and Histology, Department of Basic Biomedical Sciences, University of Bari, Bari, Italy.|National Cancer Institute "Giovanni Paolo II", Bari, Italy.
authors: Domenico
authors: D
authors: Ribatti
authors: Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors: Moritz A
authors: MA
authors: Konerding
authors: Unit of Experimental Oncology and Immunology, University of Brescia, Brescia, Italy. marco.presta@unibs.it.|Unit of Histology, Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123, Brescia, Italy. marco.presta@unibs.it.
authors: Marco
authors: M
authors: Presta
authors: CNR - Institute of Neuroscience, Milan, Italy. m.righi@in.cnr.it.|Department of Medical Biotechnology and Translational Medicine, University of Milano, Milan, Italy. m.righi@in.cnr.it.|Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Via Vanvitelli 32, 20129, Milan, Italy. m.righi@in.cnr.it.
authors: Marco
authors: M
authors: Righi
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply*; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D006801:Humans; D007443:Intussusception / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008833:Microcirculation; D055806:Microvessels / Q000503:physiopathology*
keywords: Angioarchitecture; Brain; Computational analysis; Corrosion casting; Intussusceptive angiogenesis; Neurodegenerative Krabbe disease