Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy.
Previous studies from our group, focusing on neuro-glial remodelling in human temporal lobe epilepsy (TLE), have shown the presence of immature vascular cells in various areas of the hippocampus. Here, we investigated angiogenic processes in hippocampi surgically removed from adult patients suffering from chronic intractable TLE, with various aetiologies. We compared hippocampi from TLE patients to hippocampi obtained after surgery or autopsy from non-epileptic patients (NE). We quantified the vascular density, checked for the expression of angiogenic factors and their receptors and looked for any blood-brain barrier (BBB) leakage. We used a relevant model of rat limbic epilepsy, induced by lithium-pilocarpine treatment, to understand the sequence of events. In humans, the vessel density was significantly higher in TLE than in NE patients. This was neither dependent on the aetiology nor on the degree of neuronal loss, but was positively correlated with seizure frequency. In the whole hippocampus, we observed many complex, tortuous microvessels. In the dentate gyrus, when the granular layer was dispersed, long microvessels appeared radially orientated. Vascular endothelial factor (VEGF) and tyrosine kinase receptors were detected in different types of cells. An impairment of the BBB was demonstrated by the loss of tight junctions and by Immunoglobulines G (IgG) leakage and accumulation in neurons. In the rat model of TLE, VEGF over-expression and BBB impairment occurred early after status epilepticus, followed by a progressive increase in vascularization. In humans and rodents, angiogenic processes and BBB disruption were still obvious in the chronic focus, probably activated by recurrent seizures. We suggest that the persistent leakage of serum IgG in the interstitial space and their uptake by neurons may participate in hypoperfusion and in neuronal dysfunction occurring in TLE.
Rigau
Valérie
V
Centre National de la Recherche Scientifique UMR5203, Université Montpellier 1, Université Montpellier 2, F34094 Montpellier, France.
Morin
Mélanie
M
Rousset
Marie-Claude
MC
de Bock
Frédéric
F
Lebrun
Aurore
A
Coubes
Philippe
P
Picot
Marie-Christine
MC
Baldy-Moulinier
Michel
M
Bockaert
Joël
J
Crespel
Arielle
A
Lerner-Natoli
Mireille
M
D000293:Adolescent; D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000473:pathology; D016923:Cell Death; D002648:Child; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000098:blood supply; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000473:pathology; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2