TY - JOUR
T1 - Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation
AU - Cattaruzza, F.
AU - Cottrell, G. S.
AU - Vaksman, N.
AU - Bunnett, N. W.
PY - 2009/3
Y1 - 2009/3
N2 - 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.
AB - 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.
KW - Endothelin-converting enzyme 1
KW - Neurogenic inflammation
KW - Neurokinin 1 receptor
KW - Substance P
UR - http://www.scopus.com/inward/record.url?scp=66949127237&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66949127237&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.2008.00039.x
DO - 10.1111/j.1476-5381.2008.00039.x
M3 - Article
C2 - 19222484
AN - SCOPUS:66949127237
SN - 0007-1188
VL - 156
SP - 730
EP - 739
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 5
ER -