Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

Abstract

In the past, water homeostasis of the brain was understood as a certain quantitative equilibrium of water content between intravascular, interstitial, and intracellular spaces governed mostly by hydrostatic effects i.e., strictly by physical laws. The recent achievements in molecular bioscience have led to substantial changes in this regard. Some new concepts elaborate the idea that all compartments involved in cerebral fluid homeostasis create a functional continuum with an active and precise regulation of fluid exchange between them rather than only serving as separate fluid receptacles with mere passive diffusion mechanisms, based on hydrostatic pressure. According to these concepts, aquaporin-4 (AQP4) plays the central role in cerebral fluid homeostasis, acting as a water channel protein. The AQP4 not only enables water permeability through the blood-brain barrier but also regulates water exchange between perivascular spaces and the rest of the glymphatic system, described as pan-cerebral fluid pathway interlacing macroscopic cerebrospinal fluid (CSF) spaces with the interstitial fluid of brain tissue. With regards to this, AQP4 makes water shift strongly dependent on active processes including changes in cerebral microcirculation and autoregulation of brain vessels capacity. In this paper, the role of the AQP4 as the gatekeeper, regulating the water exchange between intracellular space, glymphatic system (including the so-called neurovascular units), and intravascular compartment is reviewed. In addition, the new concepts of brain edema as a misbalance in water homeostasis are critically appraised based on the newly described role of AQP4 for fluid permeation. Finally, the relevance of these hypotheses for clinical conditions (including brain trauma and stroke) and for both new and old therapy concepts are analyzed.

Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke

“…Water transport by AQP4 is governed by the transmembrane osmotic gradient and by the rate-limiting number of AQP4 channels present in the cell membrane ( 20 ). Our understanding of AQP4 function in disease has been confounded by contradictory reports of increased or decreased expression ( 21 ). Moreover, it is unclear whether its cell-membrane localization, which is required for its function, is dynamically regulated in disease.…”

Neural activity induces strongly coupled electro-chemo-mechanical interactions and fluid flow in astrocyte networks and extracellular space—A computational study

“…Key open questions relate to the role of astrocytes in brain signaling, volume homeostasis, and clearance in general [3,16], and the role of osmotic pressures and astrocytic membrane properties on brain solute transport in particular. Specifically, there are substantial gaps in our understanding of (i) the driving forces underlying interstitial fluid movement and (ii) biophysical mechanisms for how astrocyte membrane features such as AQP4-and KIR-channels or NKCC1 co-transporters contribute to perivascular or interstitial transport [3,[16][17][18][19][20].…”

Neural activity induces strongly coupled electro-chemo-mechanical interactions and fluid flow in astrocyte networks and extracellular space – a computational study

“…Key open questions relate to the role of astrocytes in brain signaling, volume homeostasis, and clearance in general [3, 16], and the role of osmotic pressures and astrocytic membrane properties on brain solute transport in particular. Specifically, there are substantial gaps in our understanding of (i) the driving forces underlying interstitial fluid movement and (ii) biophysical mechanisms for how astrocyte membrane features such as AQP4- and KIR-channels or NKCC1 co-transporters contribute to perivascular or interstitial transport [3, 16, 17, 18, 19, 20].…”