Focal Cerebral Ischemia Preferentially Affects Neurons Distant from Their Neighboring Microvessels

Abstract

Developing cerebral infarction obscures the relationship of neurons to their local supply microvessels. We tested the notion that in the basal ganglia (i) an ordered relationship between neurons and their nearest neighboring microvessel exists, and (ii) focal ischemia predictably affects neuron integrity based on microvessel-neuron proximity. Distances between individual microvessels and their nearest neurons ([m-n distance]s) were measured in normal primates and ischemic subjects undergoing middle cerebral artery occlusion for 2 hours. An ordered microvessel-neuron relationship exists in the normal nonischemic basal ganglia within the early hours of focal ischemia. During ischemia normal (n) and sensitive (n*) neurons are interspersed. On average, neurons more distant from their nearest microvessel are most sensitive ([m-n distance] ¼ 16.2711.2 lm versus [m-n* distance] ¼ 22.2713.0 lm, 2P50.00000001). Neurons not expressing glutamic acid decarboxylase were more likely to be sensitive than those with a normal microvessel-neuron relationship. In contrast, the [m-n distance] distribution of injured tyrosine hydroxylase-containing neurons was similar to those without tyrosine hydroxylase. Hence, the [m-n distance] relationship in the normal and ischemic basal ganglia is highly ordered, and distant neurons are consistently perturbed by ischemia, although this is not uniformly dependent on neurotransmitter type.

Adult Neurogenesis and the Ischemic Forebrain

“…Mabuchi et al (2005) evaluated whether neuronal proximity to microvasculature influences neuronal integrity after focal ischemia. In the ischemic striatum in adolescent baboons, uninjured neurons reside significantly closer to neighboring microvessels than do injured neurons, identified by dUTP incorporation.…”

Heterogeneity in the penumbra

“…Ruetzler et al (2001) have shown segmental heterogeneity of central nervous system vascular responses in normoxic spontaneously hypertensive stroke-prone rats exposed to lipopolysaccharide, in which circular decoration of brain tissue by manganese superoxide dismutase was seen around some microvessels and not others. This is possibly relevant to the observations made by Mabuchi et al (2005) of an ordered, but heterogeneously distributed, neuron injury within 2 hours of MCA occlusion that is related to the microvessel supply (the 'neurovascular unit'). Of importance, these observations are not simply explained by the dependence of local injury on the fall-off of O 2 diffusion as applied to cerebral capillaries (the Krogh cylinder), but suggest other mechanisms (Quistorff et al, 1977;Mabuchi et al, 2005).…”

“…This is possibly relevant to the observations made by Mabuchi et al (2005) of an ordered, but heterogeneously distributed, neuron injury within 2 hours of MCA occlusion that is related to the microvessel supply (the 'neurovascular unit'). Of importance, these observations are not simply explained by the dependence of local injury on the fall-off of O 2 diffusion as applied to cerebral capillaries (the Krogh cylinder), but suggest other mechanisms (Quistorff et al, 1977;Mabuchi et al, 2005). Whether the coordinated expression of PCNA, integrin a v b 3 , and VEGF by cerebral microvessels during focal ischemia is an intrinsic characteristic of some vessels of a size class, or the heterogeneity of the injury, is not yet certain.…”

Blood-Brain Barrier Disruption During Acute Ischemic Stroke - The Role of Matrix Metalloproteinases and Tight Junctions Proteins

“…In the cerebral grey matter, the arterial supply is arranged in a series of hexagonal stacked arrays descending from the pial supply to the dependent capillary beds [19,20. forming a hierarchical organization similar to a honeycomb. Within the striatum the neuron-microvessel distribution is more homogenous, the capillary arrangement has branch points at approximately 30 μm intervals [21]. Within the white matter, capillaries are arranged in line with axons and comprise approximately 10% of the capillary density found within the grey matter [22].…”