title: Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries.
abstract: 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.
authors.affiliation: Toronto Centre for Microvascular Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Sonya
authors.initials: S
authors.lastname: Hui
authors.affiliation: Toronto Centre for Microvascular Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levy
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Slack
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Surgery, St. Michael's Hospital and University of Toronto, Toronto, Canada.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Burnstein
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Surgery, St. Michael's Hospital and University of Toronto, Toronto, Canada.
authors.forename: Lee
authors.initials: L
authors.lastname: Errett
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Surgery, St. Michael's Hospital and University of Toronto, Toronto, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Surgery, St. Michael's Hospital and University of Toronto, Toronto, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Latter
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Surgery, St. Michael's Hospital and University of Toronto, Toronto, Canada.
authors.forename: Ori D
authors.initials: OD
authors.lastname: Rotstein
authors.affiliation: Toronto Centre for Microvascular Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Heart & Stroke / Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Canada.
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
authors.affiliation: Toronto Centre for Microvascular Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Darcy
authors.initials: D
authors.lastname: Lidington
authors.affiliation: Toronto Centre for Microvascular Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Department of Anaesthesia, St. Michael's Hospital and University of Toronto, Toronto, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Voigtlaender-Bolz
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism*; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: C505032:CFTR protein, human; C471998:JTE 013; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C120366:sphingenine-1-phosphate; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D013110:Sphingosine