Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice

Abstract

The aquaporin-4 (AQP4) pool in the perivascular astrocyte membranes has been shown to be critically involved in the formation and dissolution of brain edema. Cerebral edema is a major cause of morbidity and mortality in stroke. It is therefore essential to know whether the perivascular pool of AQP4 is up-or down-regulated after an ischemic insult, because such changes would determine the time course of edema formation. Here we demonstrate by quantitative immunogold cytochemistry that the ischemic striatum and neocortex show distinct patterns of AQP4 expression in the reperfusion phase after 90 min of middle cerebral artery occlusion. The striatal core displays a loss of perivascular AQP4 at 24 hr of reperfusion with no sign of subsequent recovery. The most affected part of the cortex also exhibits loss of perivascular AQP4. This loss is of magnitude similar to that of the striatal core, but it shows a partial recovery toward 72 hr of reperfusion. By freeze fracture we show that the loss of perivascular AQP4 is associated with the disappearance of the square lattices of particles that normally are distinct features of the perivascular astrocyte membrane. The cortical border zone differs from the central part of the ischemic lesion by showing no loss of perivascular AQP4 at 24 hr of reperfusion but rather a slight increase. These data indicate that the size of the AQP4 pool that controls the exchange of fluid between brain and blood during edema formation and dissolution is subject to large and region-specific changes in the reperfusion phase.astrocytes ͉ brain edema ͉ ischemia ͉ stroke ͉ water channels S troke is invariably associated with a brain edema that accounts for much of the morbidity and mortality of this condition. The brain edema is often long lasting and therapyresistant and thus poses a major challenge in the clinic. A better understanding is needed of the molecular mechanisms that promote water flux across the brain-blood interface in the build-up phase and resolution phase of cerebral edema.Aquaporin-4 (AQP4) water channels are strongly enriched in the astrocyte plasma membrane domains that ensheathe the cerebral microvessels (1, 2). It was hypothesized (1) that this perivascular pool of AQP4 could become rate-limiting for water flux in pathophysiological conditions, such as in the reperfusion phase after an ischemic insult. This hypothesis was tested in a model that took advantage of the fact that the perivascular AQP4 pool is anchored through the dystrophin complex (comprising the brain dystrophin isoform DP-71 and ␣-syntrophin) (3). Mice with targeted deletion of ␣-syntrophin displayed a dramatic loss of perivascular AQP4 and a concomitant reduction in the extent of postischemic edema (4). These findings [and experiments in mdx mice (5)] support the idea that the perivascular pool of AQP4 facilitates water flux across the brain-blood interface and offer a mechanistic explanation for the reduction in brain edema formation and dissolution observed in AQP4 Ϫ/Ϫ animals (6, 7) The implication of a sp...

Glial Cell Aquaporin-4 Overexpression in Transgenic Mice Accelerates Cytotoxic Brain Swelling

“…Up-regulated AQP4 expression was also found in penetrating brain injury in rats (4) and in cortical contusion injury (3). Other studies show reduced AQP4 expression in response to various insults, including transient middle cerebral artery occlusion in rats (20,21) and diffuse (22) and focal (23) head trauma. Notwithstanding some conflicting results in the literature regarding the direction of change in AQP4 expression in various pathologies, it is concluded that brain AQP4 expression is sensitive to many types of insults, which, from the functional data here, translates to altered brain water balance.…”

Physiological Roles of Aquaporin-4 in Brain

“…The level of AQP4 in astrocytic endfeet is much depressed following transient ischemia (45,176). The reduction in AQP4 occurs with no concomitant changes in the level of ␣-syntrophin (45).…”

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

“…In other words, astrocytes may acquire barrier function and restrict water exchange between brain and blood, dependent on their complement of AQP4. This finding has direct implications for a number of experimental and clinical conditions that are characterized by a loss of perivascular AQP4, including mesial temporal lobe epilepsy (16), experimental stroke (17), and a model of Alzheimer's disease (18).…”