Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries

Broegger, Torbjoern; Jacobsen, Jens Christian Brings; Dam, Vibeke Secher; Boedtkjer, Donna Briggs; Kold-Petersen, Henrik; Pedersen, Finn Skou; Aalkjær, Christian; Matchkov, Vladimir V.

doi:10.1093/cvr/cvr111

Cited by 41 publications

(55 citation statements)

References 47 publications

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“…Wire myography on mouse aortas and mesenteric arteries (MA) was performed as described elsewhere (5,17,19). In brief, thoracic aortas and second order MA of 4-to 6-mo-old mice were carefully dissected in cold buffer (118 mmol/l NaCl, 3.4 mmol/l KCl, 1.2 mmol/l KH2PO4, 1.2 mmol/l MgSO4, 25 mmol/l NaHCO3, 11 mmol/l glucose, and 1 mmol/l CaCl 2, bubbled with 95% O2-5% CO 2) and cut into 2-mm segments.…”

Section: Methodsmentioning

confidence: 99%

The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

Schepelmann

Yarova

Lopez-Fernandez

et al. 2016

American Journal of Physiology-Cell Physiology

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-The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22␣ promoter (SM22␣-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Crepositive SM22␣ CaSR ⌬flox/⌬flox [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca 2ϩ ) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-L-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca 2ϩ concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR. calcium-sensing receptor; CaSR; vascular smooth muscle cells; blood pressure regulation; G protein-coupled receptor; blood vessel tone regulation THE EXTRACELLULAR CALCIUM -sensing receptor CaSR was the first G protein-coupled receptor identified that has an ion, Ca 2ϩ

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Section: Methodsmentioning

confidence: 99%

The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

Schepelmann

Yarova

Lopez-Fernandez

et al. 2016

American Journal of Physiology-Cell Physiology

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“…Transfection of segments of rat mesenteric small arteries in vivo was performed using a modification of our previously described method (8,32). TKO-based transfection has been used (Mirus Bio).…”

Section: Methodsmentioning

confidence: 99%

“…In the current study, we address the role of ␣ 2 for SMCs synchronization and for the control of tone in rat mesenteric small arteries. The ␣ 2 isoform was downregulated in arterial segments using a novel short interfering RNA (siRNA) transfection approach in vivo (8), and these arteries were compared with control arteries transfected with nonrelated siRNA.…”

Section: Namentioning

confidence: 99%

The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

Matchkov

Moeller-Nielsen

Dam

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Matchkov VV, Moeller-Nielsen N, Dam VS, Nourian Z, Boedtkjer DM, Aalkjaer C. The ␣2 isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries. Am J Physiol Heart Circ Physiol 303: H36 -H46, 2012. First published May 4, 2012 doi:10.1152/ajpheart.00673.2011The specific role of different isoforms of the Na,K-pump in the vascular wall is still under debate. We have previously suggested that the ␣2 isoform of the Na,K-pump (␣2), Na ϩ , Ca 2ϩ -exchange (NCX), and connexin43 form a regulatory microdomain in smooth muscle cells (SMCs), which controls intercellular communication and contractile properties of the vascular wall. We have tested this hypothesis by downregulating ␣2 in cultured SMCs and in small arteries with siRNA in vivo. Intercellular communication was assessed by using membrane capacitance measurements. Arteries transfected in vivo were tested for isometric and isobaric force development in vitro; [Ca 2ϩ ]i was measured simultaneously. Cultured rat SMCs were well-coupled electrically, but 10 M ouabain uncoupled them. Downregulation of ␣ 2 reduced electrical coupling between SMCs and made them insensitive to ouabain. Downregulation of ␣2 in small arteries was accompanied with significant reduction in NCX expression. Acetylcholine-induced relaxation was not different between the groups, but the endotheliumdependent hyperpolarizing factor-like component of the response was significantly diminished in ␣2-downregulated arteries. Micromolar ouabain reduced in a concentration-dependent manner the amplitude of norepinephrine (NE)-induced vasomotion. Sixty percent of the ␣ 2-downregulated arteries did not have vasomotion, and vasomotion in the remaining 40% was ouabain insensitive. Although ouabain increased the sensitivity to NE in the control arteries, it had no effect on ␣ 2-downregulated arteries. In the presence of a low NE concentration the ␣ 2-downregulated arteries had higher [Ca 2ϩ ]i and tone. However, the NE EC50 was reduced under isometric conditions, and maximal contraction was reduced under isometric and isobaric conditions. The latter was caused by a reduced Ca 2ϩ -sensitivity. The ␣2-downregulated arteries also had reduced contraction to vasopressin, whereas the contractile response to high K ϩ was not affected. Our results demonstrate the importance of ␣ 2 for intercellular coupling in the vascular wall and its involvement in the regulation of vascular tone. Na ϩ , Ca 2ϩ exchanger; smooth muscle cell synchronization; short interfering RNA; norepinephrine contractility; endothelium-dependent hyperpolarizing factor THE ELECTROGENIC NA,K-PUMP modifies numerous cellular pathways by modulating Na ϩ -coupled transport. The functional significance of the Na,K-pump is dependent upon the isoform. The catalytic ␣-subunit exists in three isoforms (5). These isoforms have different affinities for cardiac glycosides, kinetics, and regulation but show high structural homology and are difficult to distinguish at a fu...

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“…280 Specific knockdown of ANO1 by siRNA transfection of rat mesenteric arteries was recently demonstrated to abrogate both "classical" I Cl(Ca) and I Cl.cGMP and to inhibit spontaneous cyclical vasomotion as well as agonist-and KCl-induced contractions of small arteries. 139 Surprisingly, downregulation of ANO1 also reduced the expression at the mRNA level of bestrophins, previously shown to be involved in the generation of I Cl.cGMP and the elicitation of rhythmic vasoconstrictions in this vascular bed, 125,129 and the expression of Ca V 1.2 mRNA. The above study suggested that ANO1 plays an important function in regulating peripheral systemic vascular resistance.…”

Section: Potential Role Of Caccs and Ano1 In Pulmonary Hypertensionmentioning

confidence: 96%

Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle

et al. 2015

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Increased peripheral resistance of small distal pulmonary arteries is a hallmark signature of pulmonary hypertension (PH) and is believed to be the consequence of enhanced vasoconstriction to agonists, thickening of the arterial wall due to remodeling, and increased thrombosis. The elevation in arterial tone in PH is attributable, at least in part, to smooth muscle cells of PH patients being more depolarized and displaying higher intracellular Ca 2+ levels than cells from normal subjects. It is now clear that downregulation of voltage-dependent K + channels (e.g., Kv1.5) and increased expression and activity of voltage-dependent (Cav1.2) and voltage-independent (e.g., canonical and vanilloid transient receptor potential [TRPC and TRPV]) Ca 2+ channels play an important role in the functional remodeling of pulmonary arteries in PH. This review focuses on an anion-permeable channel that is now considered a novel excitatory mechanism in the systemic and pulmonary circulations. It is permeable to Cl − and is activated by a rise in intracellular Ca 2+ concentration (Ca 2+-activated Cl − channel, or CaCC). The first section outlines the biophysical and pharmacological properties of the channel and ends with a description of the molecular candidate genes postulated to encode for CaCCs, with particular emphasis on the bestrophin and the newly discovered TMEM16 and anoctamin families of genes. The second section provides a review of the various sources of Ca 2+ activating CaCCs, which include stimulation by mobilization from intracellular Ca 2+ stores and Ca 2+ entry through voltage-dependent and voltage-independent Ca 2+ channels. The third and final section summarizes recent findings that suggest a potentially important role for CaCCs and the gene TMEM16A in PH.Keywords: calcium-activated chloride channels, pulmonary hypertension, TMEM16A, anoctamin, bestrophin. . They are widely distributed small-conductance channels located in the plasma membrane of many cell types and are hypothesized to serve important functions in sperm maturation, fluid transport across epithelial tissues, cardiac repolarization, olfactory transduction, photoreceptor stimulation, neuronal and skeletal muscle excitation, cardiac repolarization, and vascular smooth muscle excitability and contraction. For more information on the general properties and role of CaCCs in various cell types and tissues, the reader is invited to consult excellent reviews on this topic. [1][2][3][4][5][6][7][8][9][10][11] Byrne and Large 12 were the first to report the existence of a Ca 2+ -activated Cl − conductance in smooth muscle by describing its general properties in rat anococcygeus smooth muscle. Since this initial discovery, that group and others have described this conductance in a variety of smooth muscle cells, including vascular smooth muscle cells (VSMCs). 1,4,7 The identification in 2008 by three independent groups of the TMEM16, or anoctamin, family of genes as novel candidates for CaCCs 13-15 sparked a renewed interest in refining our understan...

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Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries

Abstract: This study demonstrates the importance of bestrophins for synchronization of SMCs and strongly supports our hypothesis for generation of vasomotion.

Cited by 41 publications

References 47 publications

The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle

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Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries

Abstract: This study demonstrates the importance of bestrophins for synchronization of SMCs and strongly supports our hypothesis for generation of vasomotion.

Cited by 41 publications

References 47 publications

The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure

The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure

The α2 isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

Molecular and Functional Significance of Ca2+‐Activated Cl− Channels in Pulmonary Arterial Smooth Muscle

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The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle