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Endothelin-1 potentiates TRPV1-mediated vasoconstriction of human adipose arterioles in a protein kinase C-dependent manner
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  • Ankush Korishettar,
  • David Zhang,
  • Yoshinori Nishijima,
  • Zhihao Wang,
  • Yangjing Xie,
  • Juan Fang,
  • David Wilcox
Ankush Korishettar
Medical College of Wisconsin
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David Zhang
Medical College of Wisconsin
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Yoshinori Nishijima
Medical College of Wisconsin
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Zhihao Wang
Jilin University First Hospital
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Yangjing Xie
Medical College of Wisconsin
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Juan Fang
Medical College of Wisconsin
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David Wilcox
Medical College of Wisconsin Department of Pediatrics
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Abstract

Background: Vascular TRPV channels have emerged as important regulators of vascular tone. TRPV1 and endothelin-1 (ET-1) are independently associated with the pathophysiology of coronary vasospasm but the relationship between their vasomotor functions remains unclear. We characterized the vasomotor function of TRPV1 channels in human arterioles and investigated regulation of their vasomotor function by ET-1. Approach: Arterioles were threaded on two metal wires, equilibrated in a physiological buffer at 37 oC and exposed to increasing concentrations of capsaicin in the absence or presence of SB366791 (TRPV1-selective inhibitor) or GF109203X (PKC-selective inhibitor). Some arterioles were preconstricted with ET-1 or phenylephrine or high K+ buffer. TRPV1 mRNA and protein expression in human arteries were assessed. Results: TRPV1 transcripts and proteins were detected in human resistance arteries. Capsaicin (1 µM) induced concentration-dependent constriction of endothelium-intact (35 ± 8 %) and endothelium-denuded (43 ± 11 %) human adipose arterioles (HAA), which was significantly inhibited by SB366791 (0.2 ± 0.1 %). Preconstriction of HAA with ET-1, but not high potassium buffer or phenylephrine, significantly potentiated capsaicin-induced constriction (33 ± 7 % vs 12 ± 8 %). GF109203X significantly inhibited potentiation of capsaicin-induced constriction by ET-1. Conclusion: TRPV1 channels are expressed in the human vasculature and can influence vascular tone of human arterioles upon activation. Their vasomotor function is modulated by ET-1, mediated in part by PKC.. These findings reveal a novel interplay between ET-1 signaling and TRPV1 channels in human VSMC, adding to our understanding of the ion channel mechanisms that regulate human arteriolar tone and may also contribute to the pathophysiology of coronary vasospasm.

Peer review status:Published

14 Oct 2020Submitted to British Journal of Pharmacology
15 Oct 2020Submission Checks Completed
15 Oct 2020Assigned to Editor
19 Oct 2020Reviewer(s) Assigned
25 Oct 2020Review(s) Completed, Editorial Evaluation Pending
26 Oct 2020Editorial Decision: Revise Minor
01 Nov 20201st Revision Received
01 Nov 2020Submission Checks Completed
01 Nov 2020Assigned to Editor
01 Nov 2020Review(s) Completed, Editorial Evaluation Pending
01 Nov 2020Editorial Decision: Accept
Feb 2021Published in British Journal of Pharmacology volume 178 issue 3 on pages 709-725. 10.1111/bph.15324