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
b-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, con-
firmed 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.