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Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function.

ABSTRACT: Microcirculation homeostasis depends on several channels permeable to ions and/or small molecules that facilitate the regulation of the vasomotor tone, hyperpermeability, the blood-brain barrier, and the neurovascular coupling function. Connexin (Cxs) and Pannexin (Panxs) large-pore channel proteins are implicated in several aspects of vascular physiology. The permeation of ions (i.e., Ca²⁺) and key metabolites (ATP, prostaglandins, D-serine, etc.) through Cxs (i.e., gap junction channels or hemichannels) and Panxs proteins plays a vital role in intercellular communication and maintaining vascular homeostasis. Therefore, dysregulation or genetic pathologies associated with these channels promote deleterious tissue consequences. This review provides an overview of current knowledge concerning the physiological role of these large-pore molecule channels in microcirculation (arterioles, capillaries, venules) and in the neurovascular coupling function.

SUBMITTER: Burboa PC

PROVIDER: S-EPMC9266979 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function.

Burboa Pía C PC Puebla Mariela M Gaete Pablo S PS Durán Walter N WN Lillo Mauricio A MA

International journal of molecular sciences 20220630 13

Microcirculation homeostasis depends on several channels permeable to ions and/or small molecules that facilitate the regulation of the vasomotor tone, hyperpermeability, the blood-brain barrier, and the neurovascular coupling function. Connexin (Cxs) and Pannexin (Panxs) large-pore channel proteins are implicated in several aspects of vascular physiology. The permeation of ions (i.e., Ca<sup>2+</sup>) and key metabolites (ATP, prostaglandins, D-serine, etc.) through Cxs (i.e., gap junction chan ...[more]

PMID: 35806312

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Project description:Background and purposeControlling vascular tone involves K(+) efflux through endothelial cell small- and intermediate-conductance calcium-activated potassium channels (K(Ca)2.3 and K(Ca)3.1, respectively). We investigated the expression of these channels in astrocytes and the possibility that, by a similar mechanism, they might contribute to neurovascular coupling.Experimental approachTransgenic mice expressing enhanced green fluorescent protein (eGFP) in astrocytes were used to assess K(Ca)2.3 and K(Ca)3.1 expression by immunohistochemistry and RT-PCR. K(Ca) currents in eGFP-positive astrocytes were determined in situ using whole-cell patch clamp electrophysiology. The contribution of K(Ca)3.1 to neurovascular coupling was investigated in pharmacological experiments using electrical field stimulation (EFS) to evoke parenchymal arteriole dilatation in FVB/NJ mouse brain slices and whisker stimulation to evoke changes in cerebral blood flow in vivo, measured by laser Doppler flowmetry.Key resultsK(Ca)3.1 immunoreactivity was restricted to astrocyte processes and endfeet and RT-PCR confirmed astrocytic K(Ca)2.3 and K(Ca)3.1 mRNA expression. With 200 nM [Ca(2+)](i) , the K(Ca)2.1-2.3/K(Ca)3.1 opener NS309 increased whole-cell currents. CyPPA, a K(Ca)2.2/K(Ca)2.3 opener, was without effect. With 1 µM [Ca(2+)](i) , the K(Ca)3.1 inhibitor TRAM-34 reduced currents whereas apamin (K(Ca)2.1-2.3 blocker) had no effect. CyPPA also inhibited currents evoked by NS309 in HEK293 cells expressing K(Ca)3.1. EFS-evoked Fluo-4 fluorescence confirmed astrocyte endfoot recruitment into neurovascular coupling. TRAM-34 inhibited EFS-evoked arteriolar dilatation by 50% whereas charybdotoxin, a blocker of K(Ca)3.1 and the large-conductance K(Ca) channel, K(Ca)1.1, inhibited dilatation by 82%. TRAM-34 reduced the cortical hyperaemic response to whisker stimulation by 40%.Conclusion and implicationsAstrocytes express functional K(Ca)3.1 channels, and these contribute to neurovascular coupling.

Project description:BackgroundThe interactions between large artery function and neurovascular coupling (NVC) are emerging as important contributors to cognitive health. Women are disproportionally affected by Alzheimer's disease and related dementia later in life. Understanding large artery correlates of NVC in young women may help with preservation of cognitive health with advancing age.PurposeTo explore the association between large artery function, NVC and cognitive performance in young women.MethodsVascular measurements were made in 61 women (21 ± 4 yrs) at rest and during a cognitive challenge (Stroop task). Transcranial Doppler was used to measure left middle cerebral artery (MCA) maximum velocity (Vmax), mean velocity (Vmean), and pulsatility index (PI). NVC was determined as MCA blood velocity reactivity to the Stroop task. Large artery function was determined using carotid-femoral pulse wave velocity (cfPWV) as a proxy measure of aortic stiffness and carotid ultrasound-derived measures of compliance and reactivity (diameter change to the Stroop task). Cognitive function was assessed separately using a computerized neurocognitive battery that included appraisal of response speed, executive function, information processing efficiency, memory, attention/concentration, and impulsivity.ResultsMCA Vmax reactivity was positively associated with executive function (β = 0.26, 95% CI 0.01-0.10); MCA Vmean reactivity was negatively associated with response speed (β = -0.33, 95% CI -0.19 to -0.02) and positively with memory score (β = 0.28, 95% CI 0.01-0.19). MCA PI reactivity was negatively associated with attention performance (β = -0.29, 95% CI -14.9 to -1.0). Path analyses identified significant paths (p < 0.05) between carotid compliance and carotid diameter reactivity to select domains of cognitive function through MCA reactivity.ConclusionsNVC was associated with cognitive function in young women. Carotid artery function assessed as carotid compliance and carotid reactivity may contribute to optimal NVC in young women through increased blood flow delivery and reduced blood flow pulsatility.

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Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function.

Publications

Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function.

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