Perivascular adipose tissue-derived relaxing factors: Release by peptide agonists via proteinase-activated receptor-2 (PAR2) and non-PAR2 mechanisms

Y. Li, K. Mihara, M. Saifeddine, A. Krawetz, D. Lau, H. Li, H. Ding, C. R. Triggle, M. D. Hollenberg

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Abstract

BACKGROUND AND PURPOSE We hypothesized that proteinase-activated receptor-2 (PAR2)-mediated vasorelaxation in murine aorta tissue can be due in part to the release of adipocyte-derived relaxing factors (ADRFs). EXPERIMENTAL APPROACH Aortic rings from obese TallyHo and C57Bl6 intact or PAR2-null mice either without or with perivascular adipose tissue (PVAT) were contracted with phenylephrine and relaxation responses to PAR2-selective activating peptides (PAR2-APs: SLIGRL-NH 2 and 2-furoyl-LIGRLO-NH 2), trypsin and to PAR2-inactive peptides (LRGILS-NH 2, 2-furoyl-OLRGIL-NH 2 and LSIGRL-NH 2) were measured. Relaxation was monitored in the absence or presence of inhibitors that either alone or in combination were previously shown to inhibit ADRF-mediated responses: L-NAME (NOS), indomethacin (COX), ODQ (guanylate cyclase), catalase (H 2O 2) and the K + channel-targeted reagents, apamin, charybdotoxin, 4-aminopyridine and glibenclamide. KEY RESULTS Endothelium-intact PVAT-free preparations did not respond to PAR2-inactive peptides (LRGILS-NH 2, LSIGRL-NH 2, 2-furoyl-OLRGIL-NH 2), whereas active PAR2-APs (SLIGRL-NH 2; 2-furoyl-LIGRLO-NH 2) caused an L-NAME-inhibited relaxation. However, in PVAT-containing preparations treated with L-NAME/ODQ/indomethacin together, both PAR2-APs and trypsin caused relaxant responses in PAR2-intact, but not PAR2-null-derived tissues. The PAR2-induced PVAT-dependent relaxation (SLIGRL-NH 2) persisted in the presence of apamin plus charybdotoxin, 4-aminopyridine and glibenclamide, but was blocked by catalase, implicating a role for H 2O 2. Surprisingly, the PAR2-inactive peptides, LRGILS-NH 2 and 2-furoyl-OLRGIL-NH 2 (but not LSIGRL-NH 2), caused relaxation in PVAT-containing preparations from both PAR2-null and PAR2-intact (C57Bl, TallyHo) mice. The LRGILS-NH 2-induced relaxation was distinct from the PAR2 response, being blocked by 4-aminopyridine, but not catalase. CONCLUSIONS Distinct ADRFs that may modulate vascular tone in pathophysiological settings can be released from murine PVAT by both PAR2-dependent and PAR2-independent mechanisms.

Original languageEnglish
Pages (from-to)1990-2002
Number of pages13
JournalBritish Journal of Pharmacology
Volume164
Issue number8
DOIs
Publication statusPublished - 1 Dec 2011

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Keywords

  • PAR2
  • adipocyte-derived relaxing factor
  • catalase
  • hydrogen peroxide
  • ion channels
  • mouse
  • perivascular adipose tissue
  • potassium channels
  • protease-activated receptors
  • proteinase-activated receptors
  • relaxation

ASJC Scopus subject areas

  • Pharmacology

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