This paper reviews the local
hormone endothelin-2 (ET-2), or
vasoactive intestinal contractor (VIC), a member of the
vasoconstrictor ET
peptide family, where ET-2 is the human orthologous
peptide of the murine VIC. While ET-2/VIC gene expression has been observed in some normal tissues, ET-2 recently has been reported to act as a
tumor marker and as a
hypoxia-induced autocrine survival factor in
tumor cells. A recently published study reported that the hypoxic mimetic agent CoCl2 at 200 microM increased expression of the ET-2/VIC gene, decreased expression of the ET-1 gene, and induced intracellular
reactive oxygen species (ROS) increase and neurite outgrowth in neuronal model PC12 cells. The ROS was generated by addition of CoCl2 to the culture medium, and the CoCl2-induced effects were completely inhibited by the
antioxidant N-acetyl
cysteine. Furthermore,
interleukin-6 (IL-6) gene expression was up-regulated upon the differentiation induced by CoCl2. These results suggest that expression of ET-2/VIC and ET-1 mediated by CoCl2-induced ROS may be associated with neuronal differentiation through the regulation of
IL-6 expression. CoCl2 acts as a
pro-oxidant, as do Fe(II, III) and Cu(II). However, some
biological activities have been reported for CoCl2 that have not been observed for other
metal salts such as FeCl3, CuSO4, and NiCl2. The characteristic actions of CoCl2 may be associated with the differentiation of PC12 cells. Further elucidation of the mechanism of neurite outgrowth and regulation of ET-2/VIC expression by CoCl2 may lead to the development of treatments for neuronal disorders.