Vascular Abnormalities and the Role of Vascular Endothelial Growth Factor in the Epileptic Brain

Abstract

Epilepsy is a chronic neurological disorder generally defined to be caused by excessive neuronal activity. Thus, excessive neuronal activity is the main target of the currently used antiepileptic drugs (AEDs). However, as many as 30% of epileptic patients show drug resistance to currently available AEDs, which suggests that epilepsy should be attributed not only to neuronal cells but also to other brain cells, such as glial cells and vascular cells. Astrocytes, pericytes, and endothelial cells in particular comprise the blood-brain barrier (BBB), which tightly regulates the exchange of substances between the brain parenchyma and the circulating blood. It has been proposed that BBB dysfunction, especially barrier leakage, exacerbates epileptic progression, and conversely, that epileptic seizures induce barrier leakage. Furthermore, several studies have shown that BBB dysfunction is one of the main causes of drug resistance in epilepsy. To better understand the mechanisms that link BBB dysfunction and intractable epilepsy to gain insights for the future development of treatments, we review and discuss the relationships between epilepsy and brain vascular abnormalities, mainly by focusing on vascular malformation, BBB dysfunction, and excessive angiogenesis. Because these abnormalities have been reported to be caused by vascular endothelial growth factor (VEGF) in the ischemic brain, we discuss the possible role of VEGF in vascular abnormalities in the epileptic brain, in which the upregulation of VEGF levels has been reported. Both glial cells and endothelial cells express VEGF receptors (VEGFRs); thus, these cells are likely affected by increases in VEGF during seizures, which in turn could cause vascular abnormalities. In this review, we review the possible role of VEGF in epilepsy and discuss the mechanisms that link vascular abnormalities and intractable epilepsy.

Pathological angiogenesis and inflammation in tissues

“…Furthermore, increased VEGF levels in the CSF of PD patients has been found to be significantly correlated with BBB dysfunction and neurodegeneration (Zou et al 2017). Similarly, it is also true that barrier leakage at BBB aggravates epileptic progression and vice versa (Ogaki et al 2020). During BBB dysfunction, increased VEGF upregulates the expression of matrix metalloproteinase (MMP) in endothelial cells, which activates the VEGF/VEGFR signaling causing excessive angiogenesis in the epileptic brain (Ogaki et al 2020).…”

Simple low dose radiography allows precise lung volume assessment in mice

“…Recently, the use of lab and synchrotron radiation based micro-computed tomography (micro-CT) has been increasingly used in preclinical studies to assess quantitative parameters including lung volumes, air spaces or lesions and mean lung density 14 – 19 . These measurements have been performed in an attempt to reflect the structural and functional competence of the lung during disease progression and in response to therapy in numerous animal models of lung diseases, such as cancer, fibrosis, emphysema and transplantation 14 .…”

Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling

“…Activation of VEGF has been suggested to regulate PI3K/AKT and MEK/ERK cascades. Furthermore, VEGF is known to be involved in the trophic and neuroprotective effects of growth factors via binding to its tyrosine kinase receptors, particularly of which VEGFR2 (Flk-1) is proposed to mediate most of the neuron-specific effects of VEGF via mediating PI3K/AKT and MEK/ERK signaling [ 10 , 11 , 12 , 13 , 33 ].…”

“…Interestingly, growing evidence revealed that improving mitochondrial function with activation of PI3K/AKT and MEK/ERK pathways might tend to inhibit phosphorylation of c-Jun-NH2-terminal kinase (JNKs) and p38, the second and third major signaling cassettes in the MAPK pathway, which majorly respond to inflammatory and cellular stress to promote inflammation and cell death, in neuronal cells under many neurological conditions, both in vitro and in vivo studies [ 66 , 67 , 68 ]. Overall, MEK/ERK pathways have been reported to play a crucial role in protecting neuronal cells from death under hypoxia, global ischemia, epilepsy, status epilepticus, and Parkinson’s disease [ 33 , 63 , 68 , 69 ]. Therefore, following status epilepticus, endogenous activation of PGC-1α may regulate the VEGF/VEGFR2 (Flk-1) signaling pathway that triggers PI3K/AKT and MEK/ERK cascades and also promotes the cAMP-CREB signaling axis [ 45 , 69 ], which regulates the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family, the expression of autophagy [ 63 ] and lysosomal genes, and further contributes to neuron survival mechanisms in hippocampal neuronal cells [ 70 , 71 , 72 ].…”

“…However, whether the VEGF/VEGFR2 (Flk-1) signaling pathway contributes neurogenesis and is counteractive to epileptogenesis remains unclear [ 14 ]. Growing evidence suggests that under stressful stimuli, such as prolonged epileptic seizures, the VEGF/VEGFR2 (Flk-1) signaling pathway may participate in mediating angiogenesis, neuronal migration, hippocampal cell proliferation, and anti-apoptosis, which provide neuroprotective effects through the downstream activation of survival signaling, including phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and the mitogen activated protein kinase kinase (MEK)/mitogen activated protein kinase (ERK) [ 13 , 14 , 32 , 33 ].…”