A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo.
OBJECTIVE
We have tested the hypothesis that calcitonin gene-related peptide (CGRP) is a mediator of capsaicin-induced angiogenesis in vivo.


METHODS
In a series of experiments, the knee joints of rats were injected with CGRP, capsaicin or vehicle control. Groups of animals (n=6) were treated with the CGRP receptor antagonist BIBN4096BS and/or the NK₁ receptor antagonist SR140333. Endothelium, proliferating endothelial cell nuclei and macrophages were identified 24 h later in the synovium by immunohistochemistry and quantified by image analysis. mRNA for the receptors for CGRP and adrenomedullin were sought in normal and inflamed rat and human synovia using RT-PCR.


RESULTS
Intra-articular CGRP injection increased the endothelial cell proliferation index, whereas macrophage infiltration and knee joint diameters were similar to saline-injected controls. CGRP-induced endothelial cell proliferation was dose-dependently inhibited by BIBN4096BS. mRNA for adrenomedullin and the CGRP receptor subunits were detected in normal and inflamed human and rat synovia. In capsaicin-induced synovitis, the increased endothelial cell proliferation index was partially blocked by administration of NK₁ or CGRP antagonists individually and was reduced to the level of saline controls by coadministration of both receptor antagonists.


CONCLUSIONS
These data support the hypothesis that CGRP stimulates angiogenesis in vivo directly by activating CGRP receptors. Capsaicin-induced endothelial cell proliferation was completely blocked by coadministration of CGRP and NK₁ receptor antagonists, indicating that both CGRP and substance P may contribute to angiogenesis in this model of synovitis.
Arthritis Research UK Pain Centre, University of Nottingham, City Hospital, Nottingham, UK. paul.mapp@nottingham.ac.uk
Paul I
PI
Mapp
Daniel F
DF
McWilliams
Matthew J
MJ
Turley
Edward
E
Hargin
David A
DA
Walsh
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D051381:Rats; D017208:Rats, Wistar; D058261:Receptor Activity-Modifying Proteins / Q000235:genetics / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013582:Synovial Fluid / Q000378:metabolism; D013585:Synovitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D042501:Angiogenic Proteins; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D058286:Calcitonin Receptor-Like Protein; D058261:Receptor Activity-Modifying Proteins; D018015:Receptors, Calcitonin Gene-Related Peptide; D015740:Calcitonin Gene-Related Peptide