Cerebral Edema Formation After Stroke: Emphasis on Blood-Brain Barrier and the Lymphatic Drainage System of the Brain

Abstract

Brain edema is a severe stroke complication that is associated with prolonged hospitalization and poor outcomes. Swollen tissues in the brain compromise cerebral perfusion and may also result in transtentorial herniation. As a physical and biochemical barrier between the peripheral circulation and the central nervous system (CNS), the blood-brain barrier (BBB) plays a vital role in maintaining the stable microenvironment of the CNS. Under pathological conditions, such as ischemic stroke, the dysfunction of the BBB results in increased paracellular permeability, directly contributing to the extravasation of blood components into the brain and causing cerebral vasogenic edema. Recent studies have led to the discovery of the glymphatic system and meningeal lymphatic vessels, which provide a channel for cerebrospinal fluid (CSF) to enter the brain and drain to nearby lymph nodes and communicate with the peripheral immune system, modulating immune surveillance and brain responses. A deeper understanding of the function of the cerebral lymphatic system calls into question the known mechanisms of cerebral edema after stroke. In this review, we first discuss how BBB disruption after stroke can cause or contribute to cerebral edema from the perspective of molecular and cellular pathophysiology. Finally, we discuss how the cerebral lymphatic system participates in the formation of cerebral edema after stroke and summarize the pathophysiological process of cerebral edema formation after stroke from the two directions of the BBB and cerebral lymphatic system.

Keywords: blood-brain barrier; cerebral edema; glymphatic system; ischemic stroke; meningeal lymphatic system.

FIGURE 1

Neurovascular unit (NVU) and blood–brain barrier (BBB). (A) Transverse-section representation of the NVU. The concept of the NVU highlights the importance of the intimate interactions between components of the BBB and cells in brain parenchyma, including pericytes, astrocytes, microglia, and neurons. The BBB is centrally positioned within the NVU, which is formed by a monolayer of endothelial cells sealed by tight junctions. (B) A schematic blow-up of the tight junctions (TJs) and adherens junctions (AJs) at the BBB as defined in the text.

FIGURE 2

Three distinct phases of cerebral edema. (A) CSF influx occurred and peaked at 11.4 ± 1.8 s and 5.24 ± 0.48 min after MCAO. The first peak of CSF influx is the hydrostatic pressure gradient due to vascular obstruction. The increased PVS size triggered by spreading depolarizations (SDs) drives the second wave of perivascular CSF influx, which facilitates the swelling of astrocytic endfeet. (B) Cerebral edema can be classified into three phases: cytotoxic, ionic, and vasogenic edema phases. The cytotoxic edema phase is characterized by swelling of astrocytes and happens simultaneously with the second peak of CSF entry. The second stage of cerebral edema formation, the ionic edema stage, is mainly driven by endothelial ion channels and transporters in the context of an intact BBB, such as NKCC, NHE, KCa3.1, and Sur1-Trpm4 channel. The breakdown of BBB causes vasogenic edema. Successive alterations to the transcellular and paracellular pathway of the BBB contribute to the breakdown of BBB following stroke. First, the increase in the number of endothelial caveolae and the rate of transcytosis impairs BBB function by disturbing the transcellular pathway. Then the destruction of TJs activates the paracellular pathway. In addition to NVU cells involved in the regulation of BBB permeability, various immune cells and inflammatory factors play an important role in the destruction of TJs.

FIGURE 3

Lymphatic drainage system in the brain. (A) Meningeal lymphatic vessels run down toward the base of the skull along the sinus, the vein, and the meningeal arteries and drain out of the skull via the foramina of the base of the skull alongside arteries, veins, and cranial nerves. Meningeal lymphatic cells grow into the injured brain parenchyma induced by photochemical thrombosis. (B) Cerebrospinal fluid (CSF) enters the parenchyma by bulk flow along paravascular spaces, and ISF is cleared along paravenous drainage pathways. Meningeal lymphatic vessels absorb CSF from the adjacent subarachnoid space and ISF from the glymphatic system and transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull.