Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation

F. Cattaruzza, G. S. Cottrell, N. Vaksman, N. W. Bunnett

Research output: Contribution to journalArticlepeer-review


Background and purpose: The metalloendopeptidase endothelin-converting enzyme 1 (ECE-1) is prominently expressed in the endothelium where it converts big endothelin to endothelin-1, a vasoconstrictor peptide. Although ECE-1 is found in endosomes in endothelial cells, the role of endosomal ECE-1 is unclear. ECE-1 degrades the pro-inflammatory neuropeptide substance P (SP) in endosomes to promote recycling and re-sensitization of its neurokinin 1 (NK 1) receptor. We investigated whether ECE-1 regulates NK 1 receptor re-sensitization and the pro-inflammatory effects of SP in the endothelium. Experimental approach: We examined ECE-1 expression, SP trafficking and NK 1 receptor re-sensitization in human microvascular endothelial cells (HMEC-1), and investigated re-sensitization of SP-induced plasma extravasation in rats. Key results: HMEC-1 expressed all four ECE-1 isoforms (a-d), and fluorescent SP trafficked to early endosomes containing ECE-1b/d. The ECE-1 inhibitor SM-19712 prevented re-sensitization of SP-induced Ca 2+ signals in HMEC-1 cells. Immunoreactive ECE-1 and NK 1 receptors co-localized in microvascular endothelial cells in the rat. SP-induced extravasation of Evans blue in the urinary bladder, skin and ears of the rat desensitized when the interval between two SP injections was 10 min, and re-sensitized after 480 min. SM-19712 inhibited this re-sensitization. Conclusions and implications: By degrading endocytosed SP, ECE-1 promotes the recycling and re-sensitization of NK 1 receptors in endothelial cells, and thereby induces re-sensitization of the pro-inflammatory effects of SP. Thus, ECE-1 inhibitors may ameliorate the pro-inflammatory actions of SP.

Original languageEnglish (US)
Pages (from-to)730-739
Number of pages10
JournalBritish Journal of Pharmacology
Issue number5
StatePublished - Mar 2009


  • Endothelin-converting enzyme 1
  • Neurogenic inflammation
  • Neurokinin 1 receptor
  • Substance P

ASJC Scopus subject areas

  • Pharmacology

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