Synchrony of spontaneous Ca&lt;sup&gt;2+&lt;/sup&gt; activity in microvascular mural          cells

Mitsui, Retsu; Hashitani, Hikaru

doi:10.1540/jsmr.56.1

Cited by 13 publications

(7 citation statements)

References 61 publications

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“…Our present findings lend further support to the hypothesis that the LMCs are intrinsic pacemakers (van Helden et al, 2006;Mitsui and Hashitani, 2020) and do not require an ICC-like network to drive propagated contractions. These findings also underscore the significance of lymphatic muscle Ca 2+ handling as the driver of lymphatic pacemaking, which can be compromised in disease states leading to impaired lymphatic contractile activity (Stolarz et al, 2019;Lee et al, 2020;Van et al, 2021).…”

Section: Discussionsupporting

confidence: 90%

Characterization of the cellular components of mouse collecting lymphatic vessels reveals that lymphatic muscle cells are the innate pacemaker cells regulating lymphatic contractions

Zawieja,

Pea,

Broyhill

et al. 2023

Preprint

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Collecting lymphatic vessels (cLVs) exhibit spontaneous contractions with a pressure-dependent frequency, but the identity of the lymphatic pacemaker cell is still debated. By analogy to pacemakers in the GI and lower urinary tracts, proposed cLV pacemaker cells include interstitial cells of Cajal like cells (ICLC), pericytes, as well as the lymphatic muscle (LMCs) cells themselves. Here we tested the extent to which these cell types are invested into the mouse cLV wall and if any cell type exhibited morphological and functional processes characteristic of pacemaker cells: a contiguous network; spontaneous Ca2+ transients; and depolarization-induced propagated contractions. We employed inducible Cre (iCre) mouse models routinely used to target these specific cell populations including: c-kitCreERT2 to target ICLC; PdgfrβCreERT2 to target pericytes; PdgfrαCreERTM to target CD34+ adventitial fibroblast-like cells or ICLC; and Myh11CreERT2 to target LMCs. These specific inducible Cre lines were crossed to the fluorescent reporter ROSA26mT/mG, the genetically encoded Ca2+ sensor GCaMP6f, and the light-activated cation channel rhodopsin2 (ChR2). c-KitCreERT2 labeled both a sparse population of LECs and round adventitial cells that responded to the mast cell activator compound 48-80. PdgfrβCreERT2 drove recombination in both adventitial cells and LMCs, limiting its power to discriminate a pericyte specific population. PdgfrαCreERTM labeled a large population of interconnected, oak leaf-shaped cells primarily along the adventitial surface of the vessel. Titrated induction of the smooth muscle-specific Myh11CreERT2 revealed a LMC population with heterogeneous morphology. Only LMCs consistently, but heterogeneously, displayed spontaneous Ca2+ events during the diastolic period of the contraction cycle, and whose frequency was modulated in a pressure-dependent manner. Optogenetic depolarization through the expression of ChR2 by Myh11CreERT2, but not PdgfrαCreERTM or c-KitCreERT2, resulted in a propagated contraction. These findings support the conclusion that LMCs, or a subset of LMCs, are responsible for mouse cLV pacemaking.

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Section: Discussionsupporting

confidence: 90%

Characterization of the cellular components of mouse collecting lymphatic vessels reveals that lymphatic muscle cells are the innate pacemaker cells regulating lymphatic contractions

Zawieja,

Pea,

Broyhill

et al. 2023

Preprint

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“…A switch in the pericyte phenotype – from an excitable, electrically coupled mural cell to a non-excitable fibroblast-like cell - would have functional consequences. Electrical coupling between mural cells allows the sequential spread of depolarizations to develop synchronous calcium transients within their network (66). Because these rhythmical contractions of mural cells are required for efficient vasomotion (67), the conversion of islet pericytes, even if only a subset of them, into myofibroblasts could produce barriers for conduction of signals, interfering with effective vasodilation or vasoconstriction.…”

Section: Discussionmentioning

confidence: 99%

Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes

Gonçalves

Qadir

Boulina

et al. 2023

Preprint

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Pancreatic islets are endocrine organs that depend on their microvasculature to function properly. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here we investigated islet pericyte density, phenotype and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (Aab+; all GADA+) and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes towards pro-fibrotic myofibroblasts. Using publicly available RNAseq data, we further found that transcriptional alterations related to endothelin-1 signaling, vascular and ECM remodeling are hallmarks of single Aab+ donor pancreata. Our data show that islet pericyte/microvascular dysfunction is present at early stages of islet autoimmunity.HighlightsChanges in islet pericyte coverage and phenotype occur during T1D progression.Vascular responses to vasoactive stimuli are impaired in islets from Aab+ and T1D donors.Endothelin-1 action and receptor expression are altered in vascular cells from Aab+ and T1D donors.Strong vascular remodeling occurs in the pancreas of Aab+ and T1D donors.

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“…Moreover, it has been suggested that the muscularis mucosae found within the underlying lamina propria of some species may also be impacted by the entry of extracellular Ca 2+ ( Heppner et al, 2011 ). In addition, interstitial cells of Cajal-like cells, located within the lamina propria layers, have also demonstrated firing activity of Ca 2+ transients ( Hashitani et al, 2004 ; Johnston et al, 2008 ), and there is some influence on the activity of pericytes surrounding blood vessels within the tissue ( Mitsui and Hashitani, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

The Dependence of Urinary Bladder Responses on Extracellular Calcium Varies Between Muscarinic, Histamine, 5-HT (Serotonin), Neurokinin, Prostaglandin, and Angiotensin Receptor Activation

2022

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With many common bladder diseases arising due to abnormal contractions, a greater understanding of the receptor systems involved may aid the development of future treatments. The aim of this study was to identify any difference in the involvement of extracellular calcium (Ca2+) across prominent contractile-mediating receptors within cells lining the bladder. Strips of porcine urothelium and lamina propria were isolated from the urinary bladder dome and mounted in isolated tissue baths containing Krebs-bicarbonate solution, perfused with carbogen gas at 37°C. Tissue contractions, as well as changes to the frequency and amplitude of spontaneous activity were recorded after the addition of muscarinic, histamine, 5-hydroxytryptamine, neurokinin-A, prostaglandin E2, and angiotensin II receptor agonists in the absence and presence of 1 µM nifedipine or nominally zero Ca2+ solution. The absence of extracellular Ca2+ influx after immersion into nominally zero Ca2+ solution, or the addition of nifedipine, significantly inhibited the contractile responses (p < 0.05 for all) after stimulation with carbachol (1 µM), histamine (100 µM), 5-hydroxytryptamine (100 µM), neurokinin-A (300 nM), prostaglandin E2 (10 µM), and angiotensin II (100 nM). On average, Ca2+ influx from extracellular sources was responsible for between 20–50% of receptor-mediated contractions. This suggests that although the specific requirement of Ca2+ on contractile responses varies depending on the receptor, extracellular Ca2+ plays a key role in mediating G protein-coupled receptor contractions of the urothelium and lamina propria.

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Synchrony of spontaneous Ca<sup>2+</sup> activity in microvascular mural cells

Cited by 13 publications

References 61 publications

Characterization of the cellular components of mouse collecting lymphatic vessels reveals that lymphatic muscle cells are the innate pacemaker cells regulating lymphatic contractions

Characterization of the cellular components of mouse collecting lymphatic vessels reveals that lymphatic muscle cells are the innate pacemaker cells regulating lymphatic contractions

Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes

The Dependence of Urinary Bladder Responses on Extracellular Calcium Varies Between Muscarinic, Histamine, 5-HT (Serotonin), Neurokinin, Prostaglandin, and Angiotensin Receptor Activation

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