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

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.