title: GPCR-mediated EGF receptor transactivation regulates TRPV4 action in the vasculature.
abstract: OBJECTIVE
  Transient receptor potential vanilloid-4 (TRPV4) is a calcium-permeant ion channel that is known to affect vascular function. The ability of TRPV4 to cause a vasoconstriction in blood vessels has not yet been mechanistically examined. Further in neuronal cells, TRPV4 signalling can be potentiated by GPCR activation. Thus, we studied the mechanisms underlying the vascular contractile action of TRPV4 and the GPCR-mediated potentiation of such vasoconstriction, both of which are as yet unappreciated aspects of TRPV4 function.
  
  
  METHODS
  The mechanisms of TRPV4-dependent regulation of vascular tone in isolated mouse aortae were studied using wire myography. TRPV4-dependent calcium signalling and prostanoid production was studied in cultured human umbilical vein endothelial cells (HUVECs).
  
  
  RESULTS
  In addition to the well-documented vasorelaxation response triggered by TRPV4 activation, we report here a TRPV4-triggered vasoconstriction in the mouse aorta that involves a COX-generated Tx receptor (TP) agonist that acts in a MAPK and Src kinase signalling dependent manner. This constriction is potentiated by activation of the GPCRs for angiotensin (AT1 receptors) or proteinases (PAR1 and PAR2) via transactivation of the EGF receptor and a process involving PKC. TRPV4-dependent vascular contraction can be blocked by COX inhibitors or with TP antagonists. Further, TRPV4 activation in HUVECs stimulated Tx release as detected by an elisa.
  
  
  CONCLUSIONS
  We conclude that the GPCR potentiation of TRPV4 action and TRPV4-dependent Tx receptor activation are important regulators of vascular function and could be therapeutically targeted in vascular diseases.
authors.affiliation: Department of Physiology and Pharmacology, Inflammation Research Network and Snyder Institute for Chronic Disease, University of Calgary, Calgary, AB, Canada.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Saifeddine
authors.forename: Mahmoud
authors.initials: M
authors.lastname: El-Daly
authors.forename: Koichiro
authors.initials: K
authors.lastname: Mihara
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Peter
authors.initials: P
authors.lastname: McIntyre
authors.forename: Christophe
authors.initials: C
authors.lastname: Altier
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: Rithwik
authors.initials: R
authors.lastname: Ramachandran
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism*; D066246:ErbB Receptors / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009213:Myography; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D050916:TRPV Cation Channels / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D066246:ErbB Receptors