A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo

Br J Pharmacol. 2012 Jun;166(4):1261-71. doi: 10.1111/j.1476-5381.2012.01848.x.


Background and purpose: We have tested the hypothesis that calcitonin gene-related peptide (CGRP) is a mediator of capsaicin-induced angiogenesis in vivo.

Experimental approach: 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.

Key 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenic Proteins / antagonists & inhibitors
  • Angiogenic Proteins / chemistry
  • Angiogenic Proteins / metabolism*
  • Animals
  • Calcitonin Gene-Related Peptide / analogs & derivatives
  • Calcitonin Gene-Related Peptide / antagonists & inhibitors
  • Calcitonin Gene-Related Peptide / metabolism*
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Calcitonin Receptor-Like Protein / genetics
  • Calcitonin Receptor-Like Protein / metabolism
  • Cell Proliferation* / drug effects
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism*
  • Humans
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Rats
  • Rats, Wistar
  • Receptor Activity-Modifying Proteins / genetics
  • Receptor Activity-Modifying Proteins / metabolism
  • Receptors, Calcitonin Gene-Related Peptide / metabolism*
  • Signal Transduction / drug effects*
  • Synovial Fluid / metabolism
  • Synovitis / drug therapy
  • Synovitis / immunology
  • Synovitis / metabolism*
  • Synovitis / pathology


  • Angiogenic Proteins
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Calcitonin Receptor-Like Protein
  • Receptor Activity-Modifying Proteins
  • Receptors, Calcitonin Gene-Related Peptide
  • Calcitonin Gene-Related Peptide