Contractile Behavior of Mouse Aorta Depends on SERCA2 Isoform Distribution: Effects of Replacing SERCA2a by SERCA2b

Fransen, Paul; Chen, Jialin; Vangheluwe, Peter; Guns, Pieter-Jan

doi:10.3389/fphys.2020.00282

Cited by 6 publications

(5 citation statements)

References 38 publications

(42 reference statements)

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“…In VSMC, Orai1- and STIM1-dependent activation of SOCE can be elicited by stimulation with SERCA pump inhibitor CPA ( Ng et al, 2010 ). In the present study, it was shown that CPA-stimulated aortic rings displayed significant aortic stiffening at low cyclic stretch exposure, specifically in aged mice and independent of eNOS genotype (thereby matching the pattern of Orai1 and STIM1 gene expression reduction) and resembling the CPA effects in mice in which SERCA2a was replaced with SERCA2b ( Fransen et al, 2020 ). Our research group previously showed that SOCE in the healthy mouse aorta is insufficient to elicit significant aortic contractions ( Fransen et al, 2020 ).…”

Section: Discussionsupporting

confidence: 64%

“…In the present study, it was shown that CPA-stimulated aortic rings displayed significant aortic stiffening at low cyclic stretch exposure, specifically in aged mice and independent of eNOS genotype (thereby matching the pattern of Orai1 and STIM1 gene expression reduction) and resembling the CPA effects in mice in which SERCA2a was replaced with SERCA2b ( Fransen et al, 2020 ). Our research group previously showed that SOCE in the healthy mouse aorta is insufficient to elicit significant aortic contractions ( Fransen et al, 2020 ). This indicates that in aged arteries, reorganization of the contractile and/or adhesive apparatus of VSMC results in a higher calcium sensitivity, resulting in active aortic stiffening upon SOCE.…”

Section: Discussionsupporting

confidence: 64%

“…This could be explained by decreased filling of the SR or by inefficient emptying of the SR upon IP 3 -stimulation. SR filling is mediated by SERCA pump activity ( Fransen et al, 2020 ), and is highly dependent on the basal activity of VGCC, as previously shown ( Leloup A. J. et al, 2015 ). In the present study, we describe decreased mRNA expression of Cacna1C and ATP2A2 in aortic lysates of eNOS knockout mice, which concurs with decreased SR filling.…”

Section: Discussionmentioning

confidence: 72%

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Basal Vascular Smooth Muscle Cell Tone in eNOS Knockout Mice Can Be Reversed by Cyclic Stretch and Is Independent of Age

et al. 2022

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Introduction and Aims: Endothelial nitric oxide synthase (eNOS) knockout mice develop pronounced cardiovascular disease. In the present study, we describe the alterations in aortic physiology and biomechanics of eNOS knockout and C57Bl/6 control mice at 2–12 months of age, including a thorough physiological investigation of age and cyclic stretch-dependent VSMC contractility and aortic stiffness.Methods and Results: Peripheral blood pressure and aortic pulse wave velocity were measured in vivo, and aortic biomechanical studies and isometric contractions were investigated ex vivo. Age-dependent progression of aortic stiffness, peripheral hypertension, and aortic contractility in eNOS knockout mice was absent, attenuated, or similar to C57Bl/6 control mice. Voltage-gated calcium channel (VGCC)-dependent calcium influx inversely affected isometric contraction and aortic stiffening by α1-adrenergic stimulation in eNOS knockout mice. Baseline aortic stiffness was selectively reduced in eNOS knockout mice after ex vivo cyclic stretch exposure in an amplitude-dependent manner, which prompted us to investigate cyclic stretch dependent regulation of aortic contractility and stiffness. Aortic stiffness, both in baseline conditions and after activation of vascular smooth muscle cell (VSMC) contraction, was reduced with increasing cyclic stretch amplitude. This cyclic stretch dependency was attenuated with age, although aged eNOS knockout mice displayed better preservation of cyclic stretch-dependency compared to C57Bl/6 control mice. Store operated calcium entry-medicated aortic stiffening as induced by inhibiting sarcoplasmic reticulum calcium ATPase pumps with 10 µM CPA was most pronounced in the aorta of aged mice and at low cyclic stretch amplitude, but independent of eNOS. Basal aortic tonus and VSMC depolarization were highly dependent on eNOS, and were most pronounced at low cyclic stretch, with attenuation at increasing cyclic stretch amplitude.Conclusion: eNOS knockout mice display attenuated progression of arterial disease as compared to C57Bl/6 control mice. Basal VSMC tone in eNOS knockout mice could be reduced by ex vivo exposure to cyclic stretch through stretch-dependent regulation of cytosolic calcium. Both baseline and active aortic stiffness were highly dependent on cyclic stretch regulation, which was more pronounced in young versus aged mice. Other mediators of VSMC contraction and calcium handling were dependent on cyclic stretch mechanotransduction, but independent of eNOS.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 72%

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Basal Vascular Smooth Muscle Cell Tone in eNOS Knockout Mice Can Be Reversed by Cyclic Stretch and Is Independent of Age

et al. 2022

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“…Furthermore, cardiomyocyte Ca 2+ transporter protein expression is altered during HF in humans and animals. Notably, NCX1 and TRPC6 are usually upregulated, and SERCA2a, the predominant sarcoendoplasmic reticulum Ca 2+ pump (SERCA) isoform in the heart ( 494 ), is usually downregulated in HF ( 495 – 498 ), albeit not always ( 499 ). Since prolonged treatment with low-dose ouabain increases NCX1 expression in rat cardiomyocytes ( Fig.…”

Section: The Physiology and Pathophysiology Of Cts-nka Interactionsmentioning

confidence: 99%

Sensational site: the sodium pump ouabain-binding site and its ligands

Blaustein,

Hamlyn

2024

American Journal of Physiology-Cell Physiology

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Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950's and 60's we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, sub-nanomolar ouabain sometimes stimulates NKA whilst higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcome in HF patients. Fourth, cloning of NKA in 1985 revealed multiple NKA α and β subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent: e.g., ouabain induces hypertension in rodents while digoxin is anti-hypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous activities are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain binding site on physiology and pathophysiology.

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“…Changes of their expression results in cell malignancy, ER-stress and apoptosis [ 5 , 6 ]. Not incidentally, the first recognized task of this pump is to control relaxation in skeletal, cardiac and to some extent in smooth muscle [ 7 ]. Its role in development and differentiation has not been fully highlighted yet but it is supported by the expression of numerous isoforms.…”

Section: Introductionmentioning

confidence: 99%

The Meeting of Micropeptides with Major Ca2+ Pumps in Inner Membranes—Consideration of a New Player, SERCA1b

Zádor

2023

Membranes

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Calcium is a major signalling bivalent cation within the cell. Compartmentalization is essential for regulation of calcium mediated processes. A number of players contribute to intracellular handling of calcium, among them are the sarco/endoplasmic reticulum calcium ATP-ases (SERCAs). These molecules function in the membrane of ER/SR pumping Ca2+ from cytoplasm into the lumen of the internal store. Removal of calcium from the cytoplasm is essential for signalling and for relaxation of skeletal muscle and heart. There are three genes and over a dozen isoforms of SERCA in mammals. These can be potentially influenced by small membrane peptides, also called regulins. The discovery of micropeptides has increased in recent years, mostly because of the small ORFs found in long RNAs, annotated formerly as noncoding (lncRNAs). Several excellent works have analysed the mechanism of interaction of micropeptides with each other and with the best known SERCA1a (fast muscle) and SERCA2a (heart, slow muscle) isoforms. However, the array of tissue and developmental expressions of these potential regulators raises the question of interaction with other SERCAs. For example, the most abundant calcium pump in neonatal and regenerating skeletal muscle, SERCA1b has never been looked at with scrutiny to determine whether it is influenced by micropeptides. Further details might be interesting on the interaction of these peptides with the less studied SERCA1b isoform.

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Contractile Behavior of Mouse Aorta Depends on SERCA2 Isoform Distribution: Effects of Replacing SERCA2a by SERCA2b

Cited by 6 publications

References 38 publications

Basal Vascular Smooth Muscle Cell Tone in eNOS Knockout Mice Can Be Reversed by Cyclic Stretch and Is Independent of Age

Basal Vascular Smooth Muscle Cell Tone in eNOS Knockout Mice Can Be Reversed by Cyclic Stretch and Is Independent of Age

Sensational site: the sodium pump ouabain-binding site and its ligands

The Meeting of Micropeptides with Major Ca2+ Pumps in Inner Membranes—Consideration of a New Player, SERCA1b

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