title: Activation of neuronal transient receptor potential vanilloid 1 channel underlies 20-hydroxyeicosatetraenoic acid-induced vasoactivity: role for protein kinase A.
abstract: A rise in intraluminal pressure triggers vasoconstriction in resistance arteries, which is associated with local generation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Importantly, dysregulation of 20-HETE synthesis and activity has been implicated in several cardiovascular disease states, including ischemic disease, hypertension, and stroke; however, the exact molecular pathways involved in mediating 20-HETE bioactivity are uncertain. We investigated whether 20-HETE activates the transient receptor potential vanilloid 1 (TRPV1) and thereby regulates vascular function and blood pressure. We demonstrate that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice and by treatment with the neurokinin 1 receptor antagonist RP67580. Furthermore, we show that both channel activation (via patch-clamping of dorsal root ganglion neurons) and vessel constriction are enhanced under inflammatory conditions, and our findings indicate a predominant role for protein kinase A-mediated sensitization of TRPV1 in these phenomena. Finally, we identify a prominence of these pathway in males compared with females, an effect we relate to reduced protein kinase A-induced phosphorylation of TRPV1. 20-HETE-induced activation of TRPV1, in part, mediates pressure-induced myogenic constriction and underlies 20-HETE-induced elevations in blood pressure and coronary resistance. Our findings identify a novel vasoconstrictor 20-HETE/TRPV1 pathway that may offer potential for therapeutic targeting in cardiovascular diseases associated with elevated 20-HETE implicated in dysregulated organ blood flow, such as stroke or hypertension.
authors.affiliation: Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Sq, London EC1M 6BQ, UK.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Bubb
authors.forename: Hairuo
authors.initials: H
authors.lastname: Wen
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Panayiotou
authors.forename: Michaela
authors.initials: M
authors.lastname: Finsterbusch
authors.forename: Faiza J
authors.initials: FJ
authors.lastname: Khan
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Chan
authors.forename: John V
authors.initials: JV
authors.lastname: Priestley
authors.forename: Mark D
authors.initials: MD
authors.lastname: Baker
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D054833:Isoindoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D012727:Sex Characteristics; D050916:TRPV Cation Channels / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D054833:Isoindoles; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: blood pressure; hypertension; sensory receptor cells; sex; vasoconstriction