Elevated plasma catecholamines functionally compensate for the reduced myogenic tone in smooth muscle STIM1 knockout mice but with deleterious cardiac effects

Pichavaram, Prahalathan; Yin, Weiqiang; Evanson, Kirk W.; Jaggar, Jonathan H.; Mancarella, Salvatore

doi:10.1093/cvr/cvy015

Cited by 13 publications

(8 citation statements)

References 43 publications

(67 reference statements)

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“…Diminished arterial contractility following Stim1 knockout resulted in a drop in arterial BP, probably due to decreased total peripheral resistance. This finding differs from previous reports by other groups showing that, although myogenic tone and phenylephrine-induced vasoconstriction was blunted in mesenteric arteries from a constitutive SMC-specific STIM1-knockout model, resting BP was not affected in this model (81)(82)(83). This difference is likely due to elevated levels of circulating catecholamines, which increase HR and cardiac output and thereby compensate for diminished vascular resistance (83).…”

Section: Discussioncontrasting

confidence: 92%

STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells

Krishnan

Ali

Gonzales

et al. 2022

eLife

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Peripheral coupling between the sarcoplasmic reticulum (SR) and plasma membrane (PM) forms signaling complexes that regulate the membrane potential and contractility of vascular smooth muscle cells (VSMCs). The mechanisms responsible for these membrane interactions are poorly understood. In many cells, STIM1 (stromal-interaction molecule 1), a single transmembrane-domain protein that resides in the endoplasmic reticulum (ER), transiently moves to ER-PM junctions in response to depletion of ER Ca2+ stores and initiates store-operated Ca2+ entry (SOCE). Fully differentiated VSMCs express STIM1 but exhibit only marginal SOCE activity. We hypothesized that STIM1 is constitutively active in contractile VSMCs and maintains peripheral coupling. In support of this concept, we found that the number and size of SR-PM interacting sites were decreased, and SR-dependent Ca2+ signaling processes were disrupted in freshly isolated cerebral artery SMCs from tamoxifen-inducible, SMC-specific STIM1-knockout (Stim1-smKO) mice. VSMCs from Stim1-smKO mice also exhibited a reduction in nanoscale colocalization between Ca2+-release sites on the SR and Ca2+-activated ion channels on the PM, accompanied by diminished channel activity. Stim1-smKO mice were hypotensive, and resistance arteries isolated from them displayed blunted contractility. These data suggest that STIM1 - independent of SR Ca2+ store depletion - is critically important for stable peripheral coupling in contractile VSMCs.

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Section: Discussioncontrasting

confidence: 92%

STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells

Krishnan

Ali

Gonzales

et al. 2022

eLife

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show abstract

“…This finding differs from previous reports by other groups showing that, although myogenic tone and phenylephrine-induced vasoconstriction was blunted in mesenteric arteries from a constitutive SMC-specific STIM1-knockout model, resting BP was not affected in this model(75)(76)(77). This difference is likely due to elevated levels of circulating catecholamines, which increase HR and cardiac output and thereby compensate for diminished vascular resistance(77).In summary, our data demonstrate a vital role for STIM1 in the formation and maintenance of critical Ca 2+ -signaling microdomains in contractile VSMCs that is independent of SR Ca 2+ store depletion. Disruptions in cellular architecture at the nanoscale level associated with the loss of STIM1 resulted in arterial dysfunction and impaired BP regulation, highlighting the essential nature of SR-PM junctions in cardiovascular control.…”

contrasting

confidence: 99%

Peripheral Coupling Sites Formed by STIM1 Govern the Contractility of Vascular Smooth Muscle Cells

Krishnan

Ali

et al. 2021

Preprint

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Peripheral coupling between the sarcoplasmic reticulum (SR) and plasma membrane (PM) forms signaling complexes that regulate the membrane potential and contractility of vascular smooth muscle cells (VSMCs), although the mechanisms responsible for these membrane interactions are poorly understood. In many cells, STIM1 (stromal interaction molecule 1), a single transmembrane-domain protein that resides in the endoplasmic reticulum (ER), transiently moves to ER-PM junctions in response to depletion of ER Ca2+ stores and initiates store-operated Ca2+ entry (SOCE). Fully differentiated VSMCs express STIM1 but exhibit only marginal SOCE activity. We hypothesized that STIM1 is constitutively active in contractile VSMCs and maintains peripheral coupling. In support of this concept, we found that the number and size of SR-PM interacting sites were decreased and SR-dependent Ca2+ signaling processes were disrupted in freshly isolated cerebral artery SMCs from tamoxifen-inducible, SMC specific STIM1-knockout (Stim1-smKO) mice. VSMCs from Stim1-smKO mice also exhibited a reduction in nanoscale colocalization between Ca2+-release sites on the SR and Ca2+-activated ion channels on the PM, accompanied by diminished channel activity. Stim1-smKO mice were hypotensive and resistance arteries isolated from them displayed blunted contractility. These data suggest that STIM1 – independent of SR Ca2+ store depletion – is critically important for stable peripheral coupling in contractile VSMCs.

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“…In each cell, APs were first recorded in a control extracellular solution containing 1 nM of the βAR agonist isoproterenol (Iso) and then upon wash-on of 1 µM Iso. 1 nM Iso was used in the control solution as in previous studies (Larson et al, 2013; Peters et al, 2021) because it mimics the resting catecholamine levels in mice (Pichavaram et al, 2018; Lucot et al, 2005) and humans (Messan et al, 2017). We confirmed that 1 nM Iso did not increase AP firing rate compared to a solution lacking Iso (304 ± 15 bpm in 1 nM, N = 50 vs. 313 ± 31 bpm in 0 nM, N = 19; P = 0.9879).…”

Section: Resultsmentioning

confidence: 99%

The funny current I_f is essential for the fight-or-flight response in cardiac pacemaker cells

Peters

Rickert

Morotti

et al. 2022

Preprint

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The sympathetic nervous system fight-or-flight response is characterized by a rapid increase in heart rate, which is mediated by an increase in the spontaneous action potential (AP) firing rate of pacemaker cells in the sinoatrial node. Sympathetic neurons stimulate sinoatrial myocytes (SAMs) by activating β adrenergic receptors (βARs) and increasing cAMP. The funny current (If) is among the cAMP-sensitive currents in SAMs. If is critical for pacemaker activity, however, its role in the fight-or-flight response remains controversial. In this study, we used AP waveform analysis, machine learning, and dynamic clamp experiments in acutely-isolated SAMs from mice to quantitatively define the AP waveform changes and role of If in the fight-or-flight response. We found that while βAR stimulation significantly altered nearly all AP waveform parameters, the increase in AP firing rate was only correlated with changes in a subset of parameters (diastolic duration, late AP duration, and diastolic depolarization rate). Dynamic clamp injection of the βAR-sensitive component of If showed that it accounts for approximately 41% of the fight-or-flight increase in AP firing rate and 60% of the decrease in the interval between APs. Thus, If is an essential contributor to the fight-or-flight increase in heart rate.

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Elevated plasma catecholamines functionally compensate for the reduced myogenic tone in smooth muscle STIM1 knockout mice but with deleterious cardiac effects

Cited by 13 publications

References 43 publications

STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells

STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells

Peripheral Coupling Sites Formed by STIM1 Govern the Contractility of Vascular Smooth Muscle Cells

The funny current I_f is essential for the fight-or-flight response in cardiac pacemaker cells

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Elevated plasma catecholamines functionally compensate for the reduced myogenic tone in smooth muscle STIM1 knockout mice but with deleterious cardiac effects

Cited by 13 publications

References 43 publications

STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells

STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells

Peripheral Coupling Sites Formed by STIM1 Govern the Contractility of Vascular Smooth Muscle Cells

The funny current If is essential for the fight-or-flight response in cardiac pacemaker cells

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The funny current I_f is essential for the fight-or-flight response in cardiac pacemaker cells