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The central role of aquaporins in the pathophysiology of ischemic stroke.

Vella J, Zammit C, Di Giovanni G, Muscat R, Valentino M - Front Cell Neurosci (2015)

Bottom Line: AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome.AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction.AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biochemistry, University of Malta Msida, Malta.

ABSTRACT
Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4- mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.

No MeSH data available.


Related in: MedlinePlus

Distribution of AQP4 and coverage of cortical astrocyte microdomains at the gliovascular interface. (A) Double immunolabeling of AQP4 (red) and GFAP (green). AQP4 immunolabeling reveals that the entire network of vessels, including capillaries, is covered by astrocyte processes, albeit GFAP negative. Smaller vessels and capillaries are mostly GFAP negative but display intense labeling against the astrocyte-specific channel AQP4. The AQP4 labeling reveals continuous coverage by astrocyte end feet. Scale bar: 60 μm. Reproduced with permission from Society of Neuroscience by Simard et al. (2003). (B) Two-photon imaging of enhanced green-fluorescent protein (eGFP)-expressing astrocytes on the cortical surface in live mouse brain, illustrating the territorial astrocyte domains and the dense array of processes associated with the vasculature. The vasculature was labeled with Texas Red-dextran dye that labels the plasma and outlines the pial vasculature. Scale bar: 20 μm.
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Figure 4: Distribution of AQP4 and coverage of cortical astrocyte microdomains at the gliovascular interface. (A) Double immunolabeling of AQP4 (red) and GFAP (green). AQP4 immunolabeling reveals that the entire network of vessels, including capillaries, is covered by astrocyte processes, albeit GFAP negative. Smaller vessels and capillaries are mostly GFAP negative but display intense labeling against the astrocyte-specific channel AQP4. The AQP4 labeling reveals continuous coverage by astrocyte end feet. Scale bar: 60 μm. Reproduced with permission from Society of Neuroscience by Simard et al. (2003). (B) Two-photon imaging of enhanced green-fluorescent protein (eGFP)-expressing astrocytes on the cortical surface in live mouse brain, illustrating the territorial astrocyte domains and the dense array of processes associated with the vasculature. The vasculature was labeled with Texas Red-dextran dye that labels the plasma and outlines the pial vasculature. Scale bar: 20 μm.

Mentions: The glial membrane channel AQP4, previously named as the mercury-insensitive water channel by Verkman's group is the most abundant water channel in the brain (Papadopoulos and Verkman, 2007). It is predominantly localized in astrocyte perivascular end-feet and glial limiting membranes, at the border between the brain parenchyma and subarachnoid CSF and beneath the ependyma bordering the brain parenchyma and ventricular CSF (Papadopoulos and Verkman, 2007; Zador et al., 2009). The tight organization of astrocytes around the vasculature provides anatomical evidence that they establish exclusive territories to form very specific microdomains in brain gray matter. Such an association allows receptors and channels essential for the function of astrocytes to be densely concentrated at their vasculature. Vascular end-feet intimately plastered along the walls of larger vessels typically co-express AQP4 and glial fibrillary acidic protein (GFAP). By contrast, astrocyte end-feet in contact with capillaries are AQP positive but only occasionally GFAP-positive (Figure 4). AQP4 is not expressed in other CNS cell types such as neurons, meningeal cells or oligodendrocytes (Papadopoulos et al., 2007), but has been reported in microglia following lipopolysaccharide (LPS) injection (Tomás-Camardiel et al., 2004).


The central role of aquaporins in the pathophysiology of ischemic stroke.

Vella J, Zammit C, Di Giovanni G, Muscat R, Valentino M - Front Cell Neurosci (2015)

Distribution of AQP4 and coverage of cortical astrocyte microdomains at the gliovascular interface. (A) Double immunolabeling of AQP4 (red) and GFAP (green). AQP4 immunolabeling reveals that the entire network of vessels, including capillaries, is covered by astrocyte processes, albeit GFAP negative. Smaller vessels and capillaries are mostly GFAP negative but display intense labeling against the astrocyte-specific channel AQP4. The AQP4 labeling reveals continuous coverage by astrocyte end feet. Scale bar: 60 μm. Reproduced with permission from Society of Neuroscience by Simard et al. (2003). (B) Two-photon imaging of enhanced green-fluorescent protein (eGFP)-expressing astrocytes on the cortical surface in live mouse brain, illustrating the territorial astrocyte domains and the dense array of processes associated with the vasculature. The vasculature was labeled with Texas Red-dextran dye that labels the plasma and outlines the pial vasculature. Scale bar: 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389728&req=5

Figure 4: Distribution of AQP4 and coverage of cortical astrocyte microdomains at the gliovascular interface. (A) Double immunolabeling of AQP4 (red) and GFAP (green). AQP4 immunolabeling reveals that the entire network of vessels, including capillaries, is covered by astrocyte processes, albeit GFAP negative. Smaller vessels and capillaries are mostly GFAP negative but display intense labeling against the astrocyte-specific channel AQP4. The AQP4 labeling reveals continuous coverage by astrocyte end feet. Scale bar: 60 μm. Reproduced with permission from Society of Neuroscience by Simard et al. (2003). (B) Two-photon imaging of enhanced green-fluorescent protein (eGFP)-expressing astrocytes on the cortical surface in live mouse brain, illustrating the territorial astrocyte domains and the dense array of processes associated with the vasculature. The vasculature was labeled with Texas Red-dextran dye that labels the plasma and outlines the pial vasculature. Scale bar: 20 μm.
Mentions: The glial membrane channel AQP4, previously named as the mercury-insensitive water channel by Verkman's group is the most abundant water channel in the brain (Papadopoulos and Verkman, 2007). It is predominantly localized in astrocyte perivascular end-feet and glial limiting membranes, at the border between the brain parenchyma and subarachnoid CSF and beneath the ependyma bordering the brain parenchyma and ventricular CSF (Papadopoulos and Verkman, 2007; Zador et al., 2009). The tight organization of astrocytes around the vasculature provides anatomical evidence that they establish exclusive territories to form very specific microdomains in brain gray matter. Such an association allows receptors and channels essential for the function of astrocytes to be densely concentrated at their vasculature. Vascular end-feet intimately plastered along the walls of larger vessels typically co-express AQP4 and glial fibrillary acidic protein (GFAP). By contrast, astrocyte end-feet in contact with capillaries are AQP positive but only occasionally GFAP-positive (Figure 4). AQP4 is not expressed in other CNS cell types such as neurons, meningeal cells or oligodendrocytes (Papadopoulos et al., 2007), but has been reported in microglia following lipopolysaccharide (LPS) injection (Tomás-Camardiel et al., 2004).

Bottom Line: AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome.AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction.AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biochemistry, University of Malta Msida, Malta.

ABSTRACT
Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4- mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.

No MeSH data available.


Related in: MedlinePlus