Activation of neuronal transient receptor potential vanilloid 1 channel underlies 20-hydroxyeicosatetraenoic acid-induced vasoactivity: Role for protein kinase A

Kristen J. Bubb, Hairuo Wen, Catherine M. Panayiotou, Michaela Finsterbusch, Faiza J. Khan, Melissa V. Chan, John V. Priestley, Mark D. Baker, Amrita Ahluwalia

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)426-433
Number of pages8
JournalHypertension
Volume62
Issue number2
DOIs
Publication statusPublished - 1 Aug 2013
Externally publishedYes

Keywords

  • Blood pressure
  • Hypertension
  • Sensory receptor cells
  • Sex
  • Vasoconstriction

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