Vascular endothelial growth factor (VEGF) in seizures: a double-edged sword

Abstract

Vascular endothelial growth factor (VEGF) is a vascular growth factor which induces angiogenesis (the development of new blood vessels), vascular permeability, and inflammation. In brain, receptors for VEGF have been localized to vascular endothelium, neurons, and glia. VEGF is upregulated after hypoxic injury to the brain, which can occur during cerebral ischemia or high-altitude edema, and has been implicated in the blood-brain barrier breakdown associated with these conditions. Given its recently-described role as an inflammatory mediator, VEGF could also contribute to the inflammatory responses observed in cerebral ischemia. After seizures, blood-brain barrier breakdown and inflammation is also observed in brain, albeit on a lower scale than that observed after stroke. Recent evidence has suggested a role for inflammation in seizure disorders. We have described striking increases in VEGF protein in both neurons and glia after pilocarpine-induced status epilepticus in the brain. Increases in VEGF could contribute to the blood-brain barrier breakdown and inflammation observed after seizures. However, VEGF has also been shown to be neuroprotective across several experimental paradigms, and hence could potentially protect vulnerable cells from damage associated with seizures. Therefore, the role of VEGF after seizures could be either protective or destructive. Although only further research will determine the exact nature of VEGF's role after seizures, preliminary data indicate that VEGF plays a protective role after seizures.

Figure 1

Schematic illustrating the VEGF family of proteins and their receptors.

Figure 2

Upregulation of VEGF protein in CA1 of the hippocampus after seizures and VEGF mRNA in CA1 after cerebral ischemia. A) Control brain section stained for VEGF-ir 24h after the animal received a vehicle injection. DG = dentate gyrus. B) Post-status epilepticus (SE) (1 hour of status followed by diazepam injection) brain section stained for VEGF-ir from an animal that was perfused 24h after pilocarpine injection. C) In situ hybridization for VEGF mRNA in CA1 neurons 24h after a sham surgery. SO= stratum radiatum, SP= stratum pyramidale, SR = stratum radiatum. D) In situ hybridization for VEGF mRNA in CA1 neurons 24h after MCAO. Note that MCAO does not cause the hippocampus to be ischemic, but rather leads to indirect effects.

Figure 3

Both neurons and glia upregulate VEGF 24h after SE. All sections are stained for VEGF-ir. A schematic in the upper left shows the locations of parts A-C. A) A low (1) and high (2) magnification view of a post-SE brain section in dorsal CA1. Arrows point to glial VEGF-ir. SP = stratum pyramidale. B) Low magnification view of the entorhinal cortex of the same brain with the major layers of the medial entorhinal cortex marked. Sub = subiculum. C) Low (1), high (2), and higher (3) magnification of ventral CA3 in the same brain. Arrows point to neuronal VEGF-ir.

Figure 4

Cresyl violet stained hippocampal sections taken from animals 24 hours after status epilepticus induced by pilocarpine. A) Hippocampus from the median animal in the PBS-infused group showing damage in stratum pyramidale (SP) of area CA1. SO= stratum oriens, SR = stratum radiatum. B) Hippocampus from the median animal in the VEGF-infused group. Note the lack of cell damage in area CA1 of the animal treated with VEGF.