Roles of calcitonin gene-related peptide in ehancement of angiogenesis

Abstract

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide produced by tissue-specific alternative splicing of the primary transcript of the calcitonin/CGRP gene. CGRP is widely distributed in the central and peripheral neuronal systems and exhibits numerous biological activities in mammals. Recently, it was clarified that endogenous CGRP released from primary afferent neurons facilitates the neovascularization indispensable to tumor growth. Angiogenesis in surgical sponge models that mimics tumor stromal reaction was inhibited by a CGRP antagonist, CGRP8-37. The unilateral sciatic nerves (L 1-5) of mice were cut, and Lewis lung carcinoma (LLC) cells were implanted into the subcutaneous tissues of the legs. Tumor growth was significantly reduced in the sites of denervation of these mice, compared with the sham-operated mice. In CGRP knockout mice, the tumor growth and tumor-associated angiogenesis of implanted LLC cells were significantly reduced compared with those in wild-type mice. In LLC-bearing wild-type mice, CGRP precursor mRNA levels in the dorsal root ganglion were increased compared with those in non-LLC bearing mice. This increase was abolished by denervation. In a co-culture system using human umbilical vein endothelial cells (HUVEC) and fibroblasts, CGRP increased tube formation by endothelial cells. VEGF expression was up-regulated in the tumor implantation models in a CGRP-dependent manner. These recent results suggest that sensory nerves facilitate tumor-associated angiogenesis and tumor growth during tumor development via a release of CGRP. The same was true in the processes of wound healing and gastric ulcer healing. Further, CGRP was also reported to enhance the angiogenesis in hind-limb ischemia model. These recent results indicate CGRP may become a novel therapeutic target for controlling angiogenesis.