Abstracts

We observed that hippocampi obtained after surgery in adult patients with mesial temporal lobe epilepsy (MTLE) showed more microvessels than control hippocampi. This increase of vascularization was particularly obvious in case of granule cell dispersion (GCD), with microvessels orientating radially, parallel to the glial processes (Crespel et al., Neurosci. Lett. 2002).
Therefore, we hypothesized that a vascular remodeling was associated to the neuro-glial reorganization of the chronic focus and we attempted to evidence angiogenic processes in the adult epileptic hippocampus. We collected hippocampi from 30 patients who underwent surgery for intractable TLE (MTLE with a history of febrile seizure, or TLE with other aetiologies) and from 4 non epileptic, autopsied patients (NE).
By immunohistochemistry (IHC), we evaluated the density of microvessels and we looked for markers of cell division and immature endothelial cells. We checked the expression of angiogenic factors and their receptors (VEGF and Flk-1, Angiopoietin and Tie-2) by IHC and western blotting (WB).
We also performed IHC and WB on 2 murine models of status epilepticus-induced TLE: lithium-pilocarpine in rats and kainate in mice, to study the kinetic of vascular remodeling and its relationship with GCD, respectively. Division markers were observed in clusters of vascular cells localized in 3 areas rich in neural progenitors (Crespel et al., Neurobiol. Dis. 2005). Microvessel density was higher in epileptic patients than in NE patients; in case of MTLE with sclerosis and GCD, the vascular remodeling was intense in CA1 and the granular layer. Most of microvessels express markers of immature endothelial cells. Angiogenic factors and their receptors were detected by IHC in different types of cells. VEGF was the most expressed, mainly by neurons and often by astrocytes.
In animal models, VEGF was rapidly and strongly expressed by neurons after seizures, whereas other markers appear during the silent period. In the chronic stage, these markers were still expressed, as for human MTLE. This study demonstrates a neovascularization associated with the neuro-glial reorganization of the epileptic focus, in both Humans and Rodents. The angiogenic mechanisms involved in this pathological remodeling likely depend on the inflammatory reaction to the initial lesion. However, the expression of angiogenic markers persists in the chronic phase of epilepsy, suggesting that angiogenesis is recurrently stimulated by spontaneous seizures.
The consequences of the vascular remodeling are still unclear: beneficial by the adjustement of blood flow to the ictal neuronal metabolism or deleterious by supporting the neuro-glial reorganization ?