Gene expression profiles of ion channels and receptors in mouse resistance arteries: Effects of cell type, vascular bed, and age

Boerman, Erika M.; Sen, Sidharth; Shaw, Rebecca L.; Joshi, Trupti; Segal, Steven S.

doi:10.1111/micc.12452

Cited by 7 publications

(12 citation statements)

References 91 publications

(146 reference statements)

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“…Expression of genes for two CGRP receptor proteins, RAMP1 ( Ramp1) and CRLR ( Calcrl), was measured using quantitative real‐time PCR (qPCR) in SMCs and ECs freshly isolated from MAs of young and old mice, where age‐related changes in RAMP1 protein localization were previously demonstrated . These qPCR data were published within a supplement for a larger analysis, were re‐analyzed for the present study, and presented in Tables . In both SMCs (Table ) and ECs (Table ), Ramp1 and Calcrl transcripts were expressed at similar levels.…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether altered RyR isoform expression contributes to age‐related changes in Ca 2+ signaling, we measured the expression of Ryr1, Ryr2, and Ryr3 genes in SMCs using qPCR. These data were originally published with the above and are presented in Table . In SMCs of MAs from young mice, Ryr2 was the most highly expressed isoform (according to C T values), with less expression of Ryr1 and no detectable expression of Ryr3 (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…As described, unpaired t tests were used to compare average C T values from replicates within each age‐group. Because the genes measured for this study were included in a larger array of data, P‐values were adjusted to account for multiple comparisons using the Benjamini‐Hochberg procedure. Fold changes in gene expression in samples from old vs young mice were determined using the 2 ‐ΔΔCT method …”

Section: Methodsmentioning

confidence: 99%

“…For example, rather than contribute to their production, RyR3 may prevent Ca 2+ sparks via inhibition of RyR1 and RyR2 as shown by increased STOCs in cerebral artery SMCs from RyR3‐deficient mice . Aging increases RyR3 and decreases RyR1 mRNA expression in SMCs of mouse Mas, but whether such changes in transcript levels translate to altered protein expression or channel function is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Aging alters spontaneous and neurotransmitter‐mediated Ca²⁺ signaling in smooth muscle cells of mouse mesenteric arteries

Boerman

Segal

2020

Microcirculation

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Calcium signals mediate smooth muscle cell (SMC) contraction and relaxation, arterial diameter, and tissue blood flow. In vascular SMCs, Ca 2+ sparks entail a transient, localized increase in [Ca 2+ ] i that arises from the opening of ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) in response to increased cytosolic 1 or SR 2 [Ca 2+ ] which activates nearby large-conductance Ca 2+ -activated K + (BK Ca ) channels in the plasma membrane. These spontaneous transient outward currents (STOCs) hyperpolarize SMCs and promote vasodilation by inhibiting L-type voltage-gated Ca 2+ channels (VGCCs). 3,4 Dysfunction in spark production and coupling to BK Ca channels is evident in pathophysiological conditions including hypertension, diabetes, and hemorrhagic shock. 5 In contrast to Ca 2+ sparks, Ca 2+ waves reflect increases in [Ca 2+ ] i throughout the cytoplasm arising from Ca 2+ -and inositol 1,4,5 trisphosphate (IP 3 )-dependent Abstract Objective: Aging impairs MA dilation by reducing the ability of sensory nerves to counteract sympathetic vasoconstriction. This study tested whether altered SMC Ca 2+ signals to sympathetic (NE) and sensory (CGRP) neurotransmitters underlie aging-related deficits in vasodilation. Methods:MAs from young and old mice were pressurized and loaded with Fluo-4 dye for confocal measurement of SMC Ca 2+ sparks and waves. Endothelial denudation resolved the influence of ECs. SMCs were immunolabeled for RyR isoforms and compared with transcript levels for RyRs and CGRP receptor components.Results: SMCs from young vs old mice exhibited more spontaneous Ca 2+ spark sites with no difference in Ca 2+ waves. NE reduced spark sites and increased waves for both groups; addition of CGRP restored sparks and reduced waves only for young mice. Endothelial denudation attenuated Ca 2+ responses to CGRP for young but not old mice, which were already attenuated, suggesting a diminished role for ECs with aging. CGRP receptor expression was similar between ages with increased serum CGRP in old mice, where RyR1 expression was replaced by RyR3. Conclusion:With aging, we suggest that altered RyR expression in SMCs contributes to impaired ability of sensory neurotransmission to restore Ca 2+ signaling underlying vasomotor control during sympathetic activation. K E Y W O R D Saging, Ca 2+ signaling, perivascular nerves, vascular smooth muscle R E FE R E N C E S

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aging alters spontaneous and neurotransmitter‐mediated Ca²⁺ signaling in smooth muscle cells of mouse mesenteric arteries

Boerman

Segal

2020

Microcirculation

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“…This arrangement allows the endothelium to detect and process multiple stimuli in parallel and to generate stimulusspecific responses [30][31][32][33] . These findings, together with studies that describe molecular [34][35][36][37][38][39][40][41] and functional heterogeneity 40,42 in endothelial cells across vascular beds, and within single vessel segments, raise the possibility that dysfunctional vascular responses could arise from altered endothelial cell heterogeneity and disrupted network dynamics. Indeed, altered mulitcellular network behavior underlies disease development in a variety of physiological systems.…”

Section: Introductionmentioning

confidence: 99%

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

Wilson

Zhang

Lee

et al. 2020

Preprint

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Rationale: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations giving rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that, rather than being a population of uniformly responding cells, neighboring endothelial cells are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function.Objective: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contributes to impaired vascular reactivity in obesity. Methods and Results:To study obesity-related vascular function without the complications associated with diabetes, we induced a state of prediabetic obesity in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and network-level calcium responses. Obesity did not alter the slope of this relationship, but impaired network-level endothelial calcium responses. The network itself was comprised of structural and functional components. The structural component, a hexagonal lattice network of endothelial cells, was unchanged in obesity. The functional network contained subpopulations of clustered agonist-sensing cells from which signals were communicate through the network. In obesity there were fewer but larger clusters of agonist-sensing cells and communication path lengths between clusters was increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. Specialized subpopulations of endothelial cells had increased agonist sensitivity. These agonistresponsive cells were spatially clustered in a non-random manner and drove network level calcium responses. Communication between adjacent cells was unaltered in obesity, but there was a decrease in the size of the agonist-sensitive cell population and an increase in the clustering of agonist-responsive cells Conclusions: The distribution of cells in the endothelial network is critical in determining overall vascular function. Altered cell heterogeneity and arrangement in obesity decrease endothelial function and provide a novel framework for understanding compromised endothelial function in cardiovascular disease.

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Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

et al. 2020

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Background: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. Purpose: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. Methods and results: To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. Conclusions: The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.

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Gene expression profiles of ion channels and receptors in mouse resistance arteries: Effects of cell type, vascular bed, and age

Abstract: Differences in gene expression profiles are most pronounced between microvascular ECs and SMCs with subtle variations between vascular beds and age groups.

Cited by 7 publications

References 91 publications

Aging alters spontaneous and neurotransmitter‐mediated Ca²⁺ signaling in smooth muscle cells of mouse mesenteric arteries

Aging alters spontaneous and neurotransmitter‐mediated Ca²⁺ signaling in smooth muscle cells of mouse mesenteric arteries

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

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Gene expression profiles of ion channels and receptors in mouse resistance arteries: Effects of cell type, vascular bed, and age

Abstract: Differences in gene expression profiles are most pronounced between microvascular ECs and SMCs with subtle variations between vascular beds and age groups.

Cited by 7 publications

References 91 publications

Aging alters spontaneous and neurotransmitter‐mediated Ca2+ signaling in smooth muscle cells of mouse mesenteric arteries

Aging alters spontaneous and neurotransmitter‐mediated Ca2+ signaling in smooth muscle cells of mouse mesenteric arteries

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

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Product

Resources

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Aging alters spontaneous and neurotransmitter‐mediated Ca²⁺ signaling in smooth muscle cells of mouse mesenteric arteries

Aging alters spontaneous and neurotransmitter‐mediated Ca²⁺ signaling in smooth muscle cells of mouse mesenteric arteries