Role of aquaporin-4 in cerebral edema and stroke

Abstract

Cerebral edema plays a central role in the pathophysiology of many diseases of the central nervous system (CNS) including ischemia, trauma, tumors, inflammation, and metabolic disturbances. The formation of cerebral edema results in an increase in tissue water content and brain swelling which, if unchecked, can lead to elevated intracranial pressure (ICP), reduced cerebral blood flow, and ultimately cerebral herniation and death. Despite the clinical significance of cerebral edema, the mechanism of brain water transport and edema formation remain poorly understood. As a result, current therapeutic tools for managing cerebral edema have changed little in the past 90 years. "Malignant ischemic stroke" is characterized by high mortality (80%) and represents a major clinical problem in cerebrovascular disease. Widespread ischemic injury in these patients causes progressive cerebral edema, increased ICP, and rapid clinical decline. In response to these observations, a series of recent studies have begun to target cerebral edema in the management of large ischemic strokes. During cerebral edema formation, the glial water channel aquaporin-4 (AQP4) has been show to facilitate astrocyte swelling ("cytotoxic swelling"). AQP4 has also been seen to be responsible for the reabsorption of extracellular edema fluid ("vasogenic edema"). In the present review, the role of AQP4 in the development of cerebral edema is discussed with emphasis on its contribution to ischemic edema. We also examine the potential of AQP4 as a therapeutic target in edema associated with stroke.

Fig. 1

(a, b) Diagram depicts the structure of an AQP monomer and its clustering into tetramers. (a) Schematic demonstration of the transmembrane α-helices of AQP4 numbered from 1–6, which surround the highly selective water pore. The highly conserved “NPA” motifs are indicated. (b) AQP organizes into tetramers in the cell membrane with each unit functioning as an independent pore. (c) The distribution of CNS AQPs. AQP4 is polarized at the glial end-feet facing CSF–brain, blood–brain barrier and peri-synaptic areas. Ependymal cells have basolateral expression of AQP4. The apical processes of the choroid plexus cells are rich in AQP1 expression (adapted from Zador and Manley 2008)

Fig. 2

The bimodal role of AQP4 in the pathomechanism of cerebral edema. (a) Electron micrographs demonstrating pronounced perivascular astrocyte foot process swelling (arrows) 30 min after acute water intoxication in wild-type mice, whereas AQP4−/− mice lack cytotoxic cell swelling. (bar=3µm) (b) Wild-type mice show accelerated brain swelling and intracranial pressure increase (ICP) compared to AQP4−/− mice following IP water intoxication. Increased brain water uptake in wild-type mice is demonstrated by higher relative ICP elevation at 10 min (ΔICP_{10 min}) and significantly shorter time required to reach maximal ICP value (time to [dICP/dt]_max). (c) Reduced hemispheric enlargement in AQP4−/− mice compared to wild type controls 24 h following permanent MCA occlusion. Note the midline shift in the wild- type brain (arrow). (d) Improved functional outcome 24 h after MCA occlusion in AQP4−/−mice. (e) Cortical freeze injury disrupts the blood–brain barrier as assessed by Evans Blue extravasation and causes vasogenic edema. (f) Brain water content increase in AQP4−/− mice compared to wild-type controls in vasogenic edema

Fig. 3

Mechanism of edema formation in ischemic and hemorrhagic stroke (see text for details). In ischemic stroke (above) AQP4 facilitates water uptake of perivascular astrocyte end-feet resulting in subsequent compression of the adjacent capillary lumen. As cellular damage evolves, the mechanism shifts into vasogenic edema and later hemorrhagic conversion. During hemorrhagic stroke, factors derived from the clot act on different components of the endothelial tight junction, leading the disruption of the BBB seal. AQP4 facilitates the reabsorption of edema fluid from the extracellular space