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 (NK₁) receptor. We investigated whether ECE‐1 regulates NK₁ receptor re‐sensitization and the pro‐inflammatory effects of SP in the endothelium.

Experimental approach:  We examined ECE‐1 expression, SP trafficking and NK₁ 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 Ca²⁺ signals in HMEC‐1 cells. Immunoreactive ECE‐1 and NK₁ 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 NK₁ 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.