Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries

We recently identified sphingosine-1-phosphate (S1P) signaling and the cystic fibrosis transmembrane conductance regulator (CFTR) as prominent regulators of myogenic responsiveness in rodent resistance arteries. However, since rodent models frequently exhibit limitations with respect to human applic...

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Published in:PloS one 2015-09, Vol.10 (9), p.e0138142-e0138142
Main Authors: Hui, Sonya, Levy, Andrew S, Slack, Daniel L, Burnstein, Marcus J, Errett, Lee, Bonneau, Daniel, Latter, David, Rotstein, Ori D, Bolz, Steffen-Sebastian, Lidington, Darcy, Voigtlaender-Bolz, Julia
Format: Article
Language:English
Subjects:
Adolescent
Adult
Animal models
Animals
Arteries
Cardiology
Cardiovascular disease
Conductance
Coronary vessels
Cystic fibrosis
Cystic fibrosis transmembrane conductance regulator
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Female
Heart diseases
Heart failure
Heart surgery
Hospitals
Human behavior
Humans
Laboratory animals
Male
Medicine
Mesenteric Arteries - metabolism
Mice
Muscle Contraction - drug effects
Muscle, Smooth, Vascular - metabolism
Muscles
Musculoskeletal system
Phenylephrine
Phosphates
Physiology
Pyrazoles - pharmacology
Pyridines - pharmacology
Receptors, Lysosphingolipid - antagonists & inhibitors
Regulators
Regulatory sequences
Resistance
Rodents
Science
Signal Transduction - drug effects
Signaling
Skeletal muscle
Sphingosine
Sphingosine - metabolism
Sphingosine 1-phosphate
Stroke
Surgery
Task forces
Translation
Tumor necrosis factor-TNF
Vascular Resistance - drug effects
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cited_by cdi_FETCH-LOGICAL-c692t-1deafb1590edaa7cf3cd122f254e4b13a117b2d8841215dccfe95007b4df840d3
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container_end_page e0138142
container_issue 9
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container_title PloS one
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creator Hui, Sonya
Levy, Andrew S
Slack, Daniel L
Burnstein, Marcus J
Errett, Lee
Bonneau, Daniel
Latter, David
Rotstein, Ori D
Bolz, Steffen-Sebastian
Lidington, Darcy
Voigtlaender-Bolz, Julia
description We recently identified sphingosine-1-phosphate (S1P) signaling and the cystic fibrosis transmembrane conductance regulator (CFTR) as prominent regulators of myogenic responsiveness in rodent resistance arteries. However, since rodent models frequently exhibit limitations with respect to human applicability, translation is necessary to validate the relevance of this signaling network for clinical application. We therefore investigated the significance of these regulatory elements in human mesenteric and skeletal muscle resistance arteries. Mesenteric and skeletal muscle resistance arteries were isolated from patient tissue specimens collected during colonic or cardiac bypass surgery. Pressure myography assessments confirmed endothelial integrity, as well as stable phenylephrine and myogenic responses. Both human mesenteric and skeletal muscle resistance arteries (i) express critical S1P signaling elements, (ii) constrict in response to S1P and (iii) lose myogenic responsiveness following S1P receptor antagonism (JTE013). However, while human mesenteric arteries express CFTR, human skeletal muscle resistance arteries do not express detectable levels of CFTR protein. Consequently, modulating CFTR activity enhances myogenic responsiveness only in human mesenteric resistance arteries. We conclude that human mesenteric and skeletal muscle resistance arteries are a reliable and consistent model for translational studies. We demonstrate that the core elements of an S1P-dependent signaling network translate to human mesenteric resistance arteries. Clear species and vascular bed variations are evident, reinforcing the critical need for further translational study.
doi_str_mv 10.1371/journal.pone.0138142
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However, since rodent models frequently exhibit limitations with respect to human applicability, translation is necessary to validate the relevance of this signaling network for clinical application. We therefore investigated the significance of these regulatory elements in human mesenteric and skeletal muscle resistance arteries. Mesenteric and skeletal muscle resistance arteries were isolated from patient tissue specimens collected during colonic or cardiac bypass surgery. Pressure myography assessments confirmed endothelial integrity, as well as stable phenylephrine and myogenic responses. Both human mesenteric and skeletal muscle resistance arteries (i) express critical S1P signaling elements, (ii) constrict in response to S1P and (iii) lose myogenic responsiveness following S1P receptor antagonism (JTE013). However, while human mesenteric arteries express CFTR, human skeletal muscle resistance arteries do not express detectable levels of CFTR protein. Consequently, modulating CFTR activity enhances myogenic responsiveness only in human mesenteric resistance arteries. We conclude that human mesenteric and skeletal muscle resistance arteries are a reliable and consistent model for translational studies. We demonstrate that the core elements of an S1P-dependent signaling network translate to human mesenteric resistance arteries. Clear species and vascular bed variations are evident, reinforcing the critical need for further translational study.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26367262</pmid><doi>10.1371/journal.pone.0138142</doi><tpages>e0138142</tpages><oa>free_for_read</oa></addata></record>
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source Publicly Available Content Database; PubMed Central
subjects Adolescent
Adult
Animal models
Animals
Arteries
Cardiology
Cardiovascular disease
Conductance
Coronary vessels
Cystic fibrosis
Cystic fibrosis transmembrane conductance regulator
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Female
Heart diseases
Heart failure
Heart surgery
Hospitals
Human behavior
Humans
Laboratory animals
Male
Medicine
Mesenteric Arteries - metabolism
Mice
Muscle Contraction - drug effects
Muscle, Smooth, Vascular - metabolism
Muscles
Musculoskeletal system
Phenylephrine
Phosphates
Physiology
Pyrazoles - pharmacology
Pyridines - pharmacology
Receptors, Lysosphingolipid - antagonists & inhibitors
Regulators
Regulatory sequences
Resistance
Rodents
Science
Signal Transduction - drug effects
Signaling
Skeletal muscle
Sphingosine
Sphingosine - metabolism
Sphingosine 1-phosphate
Stroke
Surgery
Task forces
Translation
Tumor necrosis factor-TNF
Vascular Resistance - drug effects
title Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries
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