Microvascular changes associated with epilepsy: A narrative review

Abstract

The blood-brain barrier (BBB) is dysfunctional in temporal lobe epilepsy (TLE). In this regard, microvascular changes are likely present. The aim of this review is to provide an overview of the current knowledge on microvascular changes in epilepsy, and includes clinical and preclinical evidence of seizure induced angiogenesis, barriergenesis and microcirculatory alterations. Anatomical studies show increased microvascular density in the hippocampus, amygdala, and neocortex accompanied by BBB leakage in various rodent epilepsy models. In human TLE, a decrease in afferent vessels, morphologically abnormal vessels, and an increase in endothelial basement membranes have been observed. Both clinical and experimental evidence suggests that basement membrane changes, such as string vessels and protrusions, indicate and visualize a misbalance between endothelial cell proliferation and barriergenesis. Vascular endothelial growth factor (VEGF) appears to play a crucial role. Following an altered vascular anatomy, its physiological functioning is affected as expressed by neurovascular decoupling that subsequently leads to hypoperfusion, disrupted parenchymal homeostasis and potentially to seizures". Thus, epilepsy might be a condition characterized by disturbed cerebral microvasculature in which VEGF plays a pivotal role. Additional physiological data from patients is however required to validate findings from models and histological studies on patient biopsies.

Keywords: Angiogenesis; epilepsy; microvascular density; temporal lobe epilepsy; vascular endothelial growth factor.

Figure 1.

Schematic representation of processes involved in how VEGF is released and results in BBB leakage. (a) Resting situation in which VEGF is stored in large vesicles next to neurons and astrocytes. The endothelial cell barrier function is represented by adherens junctions and tight junctions formed by claudin, occludin, and ZO-1. (b) Neuronal epileptiform activity results in releasing of stored VEGF which binds to the VEGFR-2 on the endothelial cell. This activates a cascade in which PI3K and AKT are phosphorylated and activated. AKT activation results in multiple reactions. Among these are NO production, facilitated by eNOS, and mTOR activation. NO and mTOR activate hypoxia inducible factor (HIF) 1 which may be activated by hypoxia as well. HIF is a known VEGF transcription factor, therefore a positive feedback cycle of VEGF production is established. VEGFR2 activation by VEGF is known to induce matrix metalloproteinase 2 (MMP2) and MMP9, this might possibly be due to PI3K/AKT ETS-1 induction. MMP2 and MMP9 remove tight junction proteins from the cell membrane, and result in an increase in BBB permeability. The action of MMP on adherens junctions is still unknown.

Figure 2.

Schematic illustration of the possible misbalance between endothelial cell proliferation and barriergenesis. (a) Resting state in which the endothelial cells are covered with basement membrane (BM), pericytes imbedded in the BM and linked to each other with adherens- and tight-junctions. (b) MMP’s result in BM and junction breakdown. (c) VEGF, along with other factors, results in endothelial cell (EC) proliferation. (d) Barriergenesis restore the BM and pericyte coverage and junctions are formed. Excessive VEGF might result in a misbalance between (c) and (d), therefore newly formed vessels might have increased BBB permeability.