Calcium-Activated Chloride Channels in Myometrial and Vascular Smooth Muscle

Wray, Susan; Prendergast, Clodagh; Arrowsmith, Sarah

doi:10.3389/fphys.2021.751008

Cited by 16 publications

(15 citation statements)

References 127 publications

(203 reference statements)

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“…Since these 2008 reports, many studies have confirmed that TMEM16A generates functional CaCC currents in a number of vascular smooth muscle cells and thereby regulates agonist-induced vasoconstriction [ 21 , 43 , 44 , 45 ]. Moreover, it has been revealed that TMEM16A also contributes to intravascular pressure-induced myogenic depolarization and vasoconstriction in the cerebral arteries and renal arterioles of rats [ 46 , 47 ].…”

Section: Role Of Chloride Ions In Regulation Of Vascular Tone and Blo...mentioning

confidence: 99%

Chloride Ions, Vascular Function and Hypertension

Gotō

Kitazono

2022

Biomedicines

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Blood pressure is determined by cardiac output and systemic vascular resistance, and mediators that induce vasoconstriction will increase systemic vascular resistance and thus elevate blood pressure. While peripheral vascular resistance reflects a complex interaction of multiple factors, vascular ion channels and transporters play important roles in the regulation of vascular tone by modulating the membrane potential of vascular cells. In vascular smooth muscle cells, chloride ions (Cl−) are a type of anions accumulated by anion exchangers and the anion–proton cotransporter system, and efflux of Cl− through Cl− channels depolarizes the membrane and thereby triggers vasoconstriction. Among these Cl− regulatory pathways, emerging evidence suggests that upregulation of the Ca2+-activated Cl− channel TMEM16A in the vasculature contributes to the increased vascular contractility and elevated blood pressure in hypertension. A robust accumulation of intracellular Cl− in vascular smooth muscle cells through the increased activity of Na+–K+–2Cl− cotransporter 1 (NKCC1) during hypertension has also been reported. Thus, the enhanced activity of both TMEM16A and NKCC1 could act additively and sequentially to increase vascular contractility and hence blood pressure in hypertension. In this review, we discuss recent findings regarding the role of Cl− in the regulation of vascular tone and arterial blood pressure and its association with hypertension, with a particular focus on TMEM16A and NKCC1.

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Section: Role Of Chloride Ions In Regulation Of Vascular Tone and Blo...mentioning

confidence: 99%

Chloride Ions, Vascular Function and Hypertension

Gotō

Kitazono

2022

Biomedicines

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“…While we did not directly investigate these possibilities, we found changes in urinary norepinephrine were unaltered across all the genotypes examined, which suggest at least sympathetic nerve activity is unaltered by Panx1 in SMCs. The second possibility is that the vasoconstriction may be due to the capacity of Panx1 channels to facilitate anion transport across the plasma membrane, for example, Cl − 25 Although our observation that apyrase reduces EFS constriction suggests a role for extracellular ATP in vasoconstriction, we cannot completely rule out a possible additional contribution of anions such as Cl − , since changes in Cl − are a well-known mechanism to induce SMC vasoconstriction 26 and are worthy of consideration and future study for Panx1 channel activity.…”

Section: Discussionmentioning

confidence: 86%

“…The second possibility is that the vasoconstriction may be due to the capacity of Panx1 channels to facilitate anion transport across the plasma membrane, for example, Cl −25 Although our observation that apyrase reduces EFS constriction suggests a role for extracellular ATP in vasoconstriction, we cannot completely rule out a possible additional contribution of anions such as Cl − , since changes in Cl − are a well-known mechanism to induce SMC vasoconstriction 26 and are worthy of consideration and future study for Panx1 channel activity. How ATP released from SMCs participates in the vascular response to sympathetic nerve stimulation remains to be more thoroughly investigated.…”

Section: Discussionmentioning

confidence: 87%

Amount of Pannexin 1 in Smooth Muscle Cells Regulates Sympathetic Nerve–Induced Vasoconstriction

et al. 2023

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BACKGROUND: Panx1 (pannexin 1) forms high conductance channels that secrete ATP upon stimulation. The role of Panx1 in mediating constriction in response to direct sympathetic nerve stimulation is not known. Additionally, it is unknown how the expression level of Panx1 in smooth muscle cells (SMCs) influences α-adrenergic responses. We hypothesized that the amount of Panx1 in SMCs dictates the levels of sympathetic constriction and blood pressure. METHODS: To test this hypothesis, we used genetically modified mouse models enabling expression of Panx1 in vascular cells to be varied. Electrical field stimulation on isolated arteries and blood pressure were assessed. RESULTS: Genetic deletion of SMC Panx1 prevented constriction by electric field stimulation of sympathetic nerves. Conversely, overexpression of Panx1 in SMCs using a ROSA26 transgenic model increased sympathetic nerve-mediated constriction. Cx43 hemichannel inhibitors did not alter constriction. Next, we evaluated the effects of altered SMC Panx1 expression on blood pressure. To do this, we created mice combining a global Panx1 deletion, with ROSA26-Panx1 under the control of an inducible SMC specific Cre (Myh11). This resulted in mice that could express only human Panx1, only in SMCs. After tamoxifen, these mice had increased blood pressure that was acutely decreased by the Panx1 inhibitor spironolactone. Control mice genetically devoid of Panx1 did not respond to spironolactone. CONCLUSIONS: These data suggest Panx1 in SMCs could regulate the extent of sympathetic nerve constriction and blood pressure. The results also show the feasibility humanized Panx1-mouse models to test pharmacological candidates.

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“…Cl − . 24 Although our observation that apyrase blunts EFS constriction suggests a role for extracellular ATP in vasoconstriction, we cannot completely rule out a possible additional contribution of anions such as Cl − , since changes in Cl − are a well-known mechanism to induce SMC vasoconstriction 25 and are worthy of consideration and future study for Panx1 channel activity.…”

Section: Discussionmentioning

confidence: 87%

Amount of Pannexin 1 in smooth muscle cells regulates sympathetic nerve induced vasoconstriction

Dunaway

Billaud

Macal

et al. 2022

Preprint

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Pannexin 1 (Panx1) forms high conductance channels that secrete ATP upon stimulation. The role of Panx1 in mediating constriction in response to direct sympathetic nerve stimulation is not known. Additionally, it is unknown how the expression level of Panx1 in SMCs influences a-adrenergic responses. We hypothesized that the amount of Panx1 in SMCs dictates the levels of sympathetic constriction and blood pressure. To test this hypothesis, we used genetically modified mouse models enabling expression of Panx1 in vascular cells to be varied. Genetic deletion of SMC Panx1 prevented constriction by electric field stimulation of sympathetic nerves. Conversely, over-expression of Panx1 in SMCs using a ROSA26 transgenic model increased sympathetic nerve-mediated constriction. Cx43 hemichannel inhibitors did not alter constriction. Next, we evaluated the effects of altered SMC Panx1 expression on blood pressure. To do this, we created mice combining a global Panx1 deletion, with ROSA26-Panx1 under the control of an inducible SMC specific Cre (Myh11). This resulted in mice that could express only human Panx1, only in SMCs. After tamoxifen, these mice had increased blood pressure that was acutely decreased by the Panx1 inhibitor spironolactone. Control mice genetically devoid of Panx1 did not respond to spironolactone. These data suggest Panx1 in SMCs could regulate the extent of sympathetic nerve constriction and blood pressure. The results also show the feasibility humanized Panx1-mouse models to test pharmacological candidates.

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Calcium-Activated Chloride Channels in Myometrial and Vascular Smooth Muscle

Cited by 16 publications

References 127 publications

Chloride Ions, Vascular Function and Hypertension

Chloride Ions, Vascular Function and Hypertension

Amount of Pannexin 1 in Smooth Muscle Cells Regulates Sympathetic Nerve–Induced Vasoconstriction

Amount of Pannexin 1 in smooth muscle cells regulates sympathetic nerve induced vasoconstriction

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