Seizure‐induced microvascular injury is associated with impaired neurovascular coupling and blood–brain barrier dysfunction

Abstract

Summary Objective Blood–brain barrier (BBB) impairment, redistribution of pericytes, and disturbances in cerebral blood flow may contribute to the increased seizure propensity and neurological comorbidities associated with epilepsy. However, despite the growing evidence of postictal disturbances in microcirculation, it is not known how recurrent seizures influence pericytic membrane currents and subsequent vasodilation. Methods Here, we investigated successive changes in capillary neurovascular coupling and BBB integrity during recurrent seizures induced by 4‐aminopyridine or low‐Mg2+ conditions. To avoid the influence of arteriolar dilation and cerebral blood flow changes on the capillary response, we measured seizure‐associated pericytic membrane currents, capillary motility, and permeability changes in a brain slice preparation. Arteriolar responses to 4‐aminopyridine–induced seizures were further studied in anesthetized Sprague Dawley rats by using electrocorticography and tissue oxygen recordings simultaneously with intravital imaging of arteriolar diameter, BBB permeability, and cellular damage. Results Within the preserved vascular network in hippocampal slice cultures, pericytes regulated capillary diameter in response to vasoactive agents and neuronal activity. Seizures induced distinct patterns of membrane currents that contributed to the regulation of pericytic length. During the course of recurrent seizures, individual vasodilation responses eroded and BBB permeability increased, despite unaltered neurometabolic coupling. Reduced vascular responsiveness was associated with mitochondrial depolarization in pericytes. Subsequent capillary constriction preceded BBB opening, suggesting that pericyte injury mediates the breach in capillary integrity. In vivo findings were consistent with slice experiments, showing seizure‐related neurovascular decoupling and BBB dysfunction in small cortical arterioles, accompanied by perivascular cellular injury despite normoxic conditions. Significance Our study presents a direct observation of gradually developing neurovascular decoupling during recurrent seizures and suggests pericytic injury as an inducer of vascular dysfunction in epilepsy.

A pericyte‐glia scarring develops at the leaky capillaries in the hippocampus during seizure activity

“…We propose PDGFRβ modulation as a possible strategy to limit inflammation as induced by seizure activity. The formation of localized pockets of rigid scar tissue at the outer capillary wall could represent a mechanism for the reported abnormal vascular tone control and neurovascular coupling in epilepsy …”

“…The formation of localized pockets of rigid scar tissue at the outer capillary wall could represent a mechanism for the reported abnormal vascular tone control 7 and neurovascular coupling in epilepsy. 10 As we used an experimental model of TLE associated with hippocampal sclerosis, our data provide insights on the cellular dynamics contributing to disease progression, graphically represented in Figure 5F. Here we extend the current knowledge of glial scarring 36,37 and pericyte reactivity 9 in epilepsy by showing: (a) a buildup of microglial cells at the hippocampal capillary where pericytosis and astrogliosis occur; (b) pericyte participation in the formation of perivascular glial scar during seizure progression in a model of TLE; and (c) the occurrence of fibrotic changes involving PDGFRβ stromal cells in the proximity of capillaries and damaged pericytes during epileptogenesis.…”

“…We previously reported that in response to status epilepticus (SE) and during epileptogenesis, cerebrovascular pericytes or smooth muscle cells undergo redistribution and remodeling, potentially contributing to BBB permeability . During seizures, pericyte damage negatively impacts neurovascular coupling . Starting from this evidence we tested the hypothesis that, in a model of temporal lobe epilepsy (TLE) associated with hippocampal sclerosis, reactive astrocytes, pericytes, and microglial cells cluster around the capillaries to form scarring microregions.…”

“…[7][8][9] During seizures, pericyte damage negatively impacts neurovascular coupling. 10 Starting from this evidence we tested the hypothesis that, in a model of temporal lobe epilepsy (TLE) associated with hippocampal sclerosis, reactive astrocytes, pericytes, and microglial cells cluster around the capillaries to form scarring microregions. We analyzed the contribution of platelet-derived growth factor receptor beta (PDGFRβ) cells and collagens to the perivascular multicellular reactivity.…”

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

“…MMPs likely affect barrier integrity by digesting and remodeling the extracellular matrix surrounding brain capillaries and by degrading tight junction proteins that seal the endothelium [38,39]. Induction of seizures was also shown to induce inward current in pericytes leading to altered pericytic functions and BBB properties in vitro and in vivo [40]. As illustrated in Figure 2, glutamate release, reactive oxygen species (ROS), MMPs, angiogenic factors, inflammatory cytokines, autoantibodies, leukocyte adhesion and immune cell extravasation have all been discussed in this regard [5,40].…”