title: Endothelial Ca2+ wavelets and the induction of myoendothelial feedback.
abstract: When arteries constrict to agonists, the endothelium inversely responds, attenuating the initial vasomotor response. The basis of this feedback mechanism remains uncertain, although past studies suggest a key role for myoendothelial communication in the signaling process. The present study examined whether second messenger flux through myoendothelial gap junctions initiates a negative-feedback response in hamster retractor muscle feed arteries. We specifically hypothesized that when agonists elicit depolarization and a rise in second messenger concentration, inositol trisphosphate (IP(3)) flux activates a discrete pool of IP(3) receptors (IP(3)Rs), elicits localized endothelial Ca(2+) transients, and activates downstream effectors to moderate constriction. With use of integrated experimental techniques, this study provided three sets of supporting observations. Beginning at the functional level, we showed that blocking intermediate-conductance Ca(2+)-activated K(+) channels (IK) and Ca(2+) mobilization from the endoplasmic reticulum (ER) enhanced the contractile/electrical responsiveness of feed arteries to phenylephrine. Next, structural analysis confirmed that endothelial projections make contact with the overlying smooth muscle. These projections retained membranous ER networks, and IP(3)Rs and IK channels localized in or near this structure. Finally, Ca(2+) imaging revealed that phenylephrine induced discrete endothelial Ca(2+) events through IP(3)R activation. These events were termed recruitable Ca(2+) wavelets on the basis of their spatiotemporal characteristics. From these findings, we conclude that IP(3) flux across myoendothelial gap junctions is sufficient to induce focal Ca(2+) release from IP(3)Rs and activate a discrete pool of IK channels within or near endothelial projections. The resulting hyperpolarization feeds back on smooth muscle to moderate agonist-induced depolarization and constriction.
authors.affiliation: Hotchkiss Brain and Libin Cardiovascular Research Institute, Department of Physiology and Pharmacology, University of Calgary, Canada.
authors.forename: Cam Ha T
authors.initials: CH
authors.lastname: Tran
authors.forename: Mark S
authors.initials: MS
authors.lastname: Taylor
authors.forename: Frances
authors.initials: F
authors.lastname: Plane
authors.forename: Sridevi
authors.initials: S
authors.lastname: Nagaraja
authors.forename: Nikolaos M
authors.initials: NM
authors.lastname: Tsoukias
authors.forename: Viktoryiya
authors.initials: V
authors.lastname: Solodushko
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Vigmond
authors.forename: Tobias
authors.initials: T
authors.lastname: Furstenhaupt
authors.forename: Mathew
authors.initials: M
authors.lastname: Brigdan
authors.forename: Donald G
authors.initials: DG
authors.lastname: Welsh
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005246:Feedback / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008647:Mesocricetus; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D053496:Inositol 1,4,5-Trisphosphate Receptors; D024681:Potassium Channels, Calcium-Activated; D010656:Phenylephrine; D002118:Calcium