Impaired endothelial calcium signaling is responsible for the defective dilation of mesenteric resistance arteries from db/db mice to acetylcholine

Chen, Hua; Kold-Petersen, Henrik; Laher, Ismail; Simonsen, Ulf; Aalkjær, Christian

doi:10.1016/j.ejphar.2015.09.043

Cited by 12 publications

(16 citation statements)

References 24 publications

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“…Flow 41 and Ach 56 induce endothelium-dependent dilations through different coupling partners and intracellular pathways. Activation of muscarinic subtype-3 receptors 57 coupled to Gq proteins 58 increases intracellular Ca 2þ , 56 likely accounting for Ach-mediated dilation in mouse arteries. Flow, however, increases Akt-dependent phosphorylation of eNOS and enhances its activity, while the involvement of intracellular Ca 2þ is unclear.…”

Section: Discussionmentioning

confidence: 99%

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Raignault

Bolduc

Lesage

et al. 2016

J Cereb Blood Flow Metab

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Arterial blood pressure is oscillatory; whether pulse pressure (PP) regulates cerebral artery myogenic tone (MT) and endothelial function is currently unknown. To test the impact of PP on MT and dilation to flow (FMD) or to acetylcholine (Ach), isolated pressurized mouse posterior cerebral arteries were subjected to either static pressure (SP) or a physiological PP (amplitude: 30 mm Hg; frequency: 550 bpm). Under PP, MT was significantly higher than in SP conditions (p < 0.05) and was not affected by eNOS inhibition. In contrast, under SP, eNOS inhibition increased (p < 0.05) MT to levels observed under PP, suggesting that PP may inhibit eNOS. At a shear stress of 20 dyn/cm 2 , FMD was lower (p < 0.05) under SP than PP. Under SP, eNOS-dependent O À 2 =H 2 O 2 production contributed to FMD, while under PP, eNOS-dependent NO was responsible for FMD, indicating that PP favours eNOS coupling. Differences in FMD between pressure conditions were abolished after NOX2 inhibition. In contrast to FMD, Ach-induced dilations were higher (p < 0.05) under SP than PP. Reactive oxygen species scavenging reduced (p < 0.05) Ach-dependent dilations under SP, but increased (p < 0.05) them under PP; hence, under PP, Ach promotes ROS production and limits eNOS-derived NO activity. In conclusion, PP finely regulates eNOS, controlling cerebral artery reactivity.

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Section: Discussionmentioning

confidence: 99%

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Raignault

Bolduc

Lesage

et al. 2016

J Cereb Blood Flow Metab

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“…Nitric oxide (NO) derived from the endothelium has a variety of functions including regulation of vascular tone, inhibition of platelet aggregation and adhesion of inflammatory leukocytes to the endothelial cells, and therefore endothelial dysfunction is thought to be of importance for the development of atherosclerosis and nephropathy in diabetes (Paneni et al, 2013). In animal models and humans with types 1 and 2 diabetes mellitus, endothelium-dependent vasodilatation is impaired in both large and small arteries (Caballero et al, 1999;Pannirselvam et al, 2002;Gao et al, 2007Gao et al, , 2008Zhang et al, 2008;Bagi et al, 2015;Chen et al, 2015;Lee et al, 2017;Katare et al, 2018). Acute hyperglycaemia is also associated with impaired endotheliumdependent vasodilatation and decreased NO bioavailability (Brodsky et al, 2017), and inactivation of NO by oxygen-derived free radical species is thought to be an important mechanism in this condition (Pannirselvam et al, 2002;Gao et al, 2007;Paneni et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Endothelial Dysfunction and Passive Changes in the Aorta and Coronary Arteries of Diabetic db/db Mice

Beck

Comerma-Steffensen

et al. 2020

Front. Physiol.

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Endothelial cell dysfunction and vessel stiffening are associated with a worsened prognosis in diabetic patients with cardiovascular diseases. The present study hypothesized that sex impacts endothelial dysfunction and structural changes in arteries from diabetic mice. In diabetic (db/db) and normoglycaemic (db/db+) mice, the mechanical properties were investigated in pressurized isolated left anterior descending coronary arteries and aorta segments that were subjected to tensile testing. Functional studies were performed on wire-mounted vascular segments. The male and female db/db mice were hyperglycaemic and had markedly increased body weight. In isolated aorta segments without the contribution of smooth muscle cells, load to rupture, viscoelasticity, and collagen content were decreased suggesting larger distensibility of the arterial wall in both male and female db/db mice. In male db/db aorta segments with smooth muscle cell contribution, lumen diameter was smaller and the passive stretch-tension curve was leftward-shifted, while they were unaltered in female db/db aorta segments versus control db/db+ mice. In contrast to female db/db mice, coronary arteries from male db/db mice had altered stress-strain relationships and increased distensibility. Transthoracic echocardiography revealed a dilated left ventricle with unaltered cardiac output, while aortic flow velocity was decreased in male db/db mice. Impairment of acetylcholine relaxation was aggravated in aorta from female db/db compared to control and male db/db mice, while impairment of sodium nitroprusside relaxations was only observed in aorta from male db/db mice. The remodeling in the coronary arteries and aorta suggests an adaptation of the arterial wall to the reduced flow velocity with sex-specific differences in the passive properties of aorta and coronary arteries. The findings of less distensible arteries and more pronounced endothelial dysfunction in female compared to male diabetic mice may have implications for the observed higher incidence of macrovascular complications in diabetic women.

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“…The universal involvement of calcium ranges from basic physiological processes such as muscle contraction, neuronal discharge and pancreatic secretion, to early development events including mammalian egg fertilization and embryonic pattern formation (Berridge et al, 2000). Calcium signaling is also known to be impaired in various pathological states, as suggested for metabolic acidosis in this study, chronic renal failure (Massry et al, 1995), Alzheimer's (Brawek et al, 2014), Diabetes (Chen et al, 2015), and zinc deficiency (O'Dell and Browning, 2013). However, despite all that we know about calcium's role in biological processes, there remains ongoing debate on how calcium signals robustly encode information while still exhibiting a large degree of heterogeneity within and between various cellular populations.…”

Section: Discussionmentioning

confidence: 53%

Systematic Characterization of Dynamic Parameters of Intracellular Calcium Signals

et al. 2016

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Dynamic processes, such as intracellular calcium signaling, are hallmark of cellular biology. As real-time imaging modalities become widespread, a need for analytical tools to reliably characterize time-series data without prior knowledge of the nature of the recordings becomes more pressing. The goal of this study is to develop a signal-processing algorithm for MATLAB that autonomously computes the parameters characterizing prominent single transient responses (TR) and/or multi-peaks responses (MPR). The algorithm corrects for signal contamination and decomposes experimental recordings into contributions from drift, TRs, and MPRs. It subsequently provides numerical estimates for the following parameters: time of onset after stimulus application, activation time (time for signal to increase from 10 to 90% of peak), and amplitude of response. It also provides characterization of the (i) TRs by quantifying their area under the curve (AUC), response duration (time between 1/2 amplitude on ascent and descent of the transient), and decay constant of the exponential decay region of the deactivation phase of the response, and (ii) MPRs by quantifying the number of peaks, mean peak magnitude, mean periodicity, standard deviation of periodicity, oscillatory persistence (time between first and last discernable peak), and duty cycle (fraction of period during which system is active) for all the peaks in the signal, as well as coherent oscillations (i.e., deterministic spikes). We demonstrate that the signal detection performance of this algorithm is in agreement with user-mediated detection and that parameter estimates obtained manually and algorithmically are correlated. We then apply this algorithm to study how metabolic acidosis affects purinergic (P2) receptor-mediated calcium signaling in osteoclast precursor cells. Our results reveal that acidosis significantly attenuates the amplitude and AUC calcium responses at high ATP concentrations. Collectively, our data validated this algorithm as a general framework for comprehensively analyzing dynamic time-series.

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Impaired endothelial calcium signaling is responsible for the defective dilation of mesenteric resistance arteries from db/db mice to acetylcholine

Cited by 12 publications

References 24 publications

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Endothelial Dysfunction and Passive Changes in the Aorta and Coronary Arteries of Diabetic db/db Mice

Systematic Characterization of Dynamic Parameters of Intracellular Calcium Signals

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