Issue 69, 2020, Issue in Progress

Zn(ii)2,9-dimethyl-1,10-phenanthroline stimulates cultured bovine aortic endothelial cell proliferation


Vascular endothelial cells cover the luminal surface of blood vessels in a monolayer. Proliferation of these cells is crucial for the repair of damaged endothelial monolayers. In the present study, we identified a zinc complex, Zn(II)2,9-dimethyl-1,10-phenanthroline (Zn-12), that stimulates the proliferation of bovine aortic endothelial cells in a culture system. No such stimulatory activity was observed for the ligand alone or in combination with other metals; however, the ligand combined with iron weakly stimulated the proliferation, as evidenced by the [3H]thymidine incorporation assay. Inorganic zinc weakly but significantly stimulated proliferation, and intracellular accumulation of zinc was similar between inorganic zinc and Zn-12 treatment, suggesting that the mechanisms by which Zn-12 stimulates vascular endothelial cell proliferation contain processes that differ from those by which inorganic zinc stimulates proliferation. Although expression of endogenous fibroblast growth factor-2 (FGF-2) and its receptor FGFR-1 was unchanged by Zn-12, both siRNA-mediated knockdown of FGF-2 and FGFR inhibition partly but significantly suppressed the stimulation of vascular endothelial cell proliferation by Zn-12, indicating that the zinc complex activates the FGF-2 pathway to stimulate proliferation. Phosphorylation of ERK1/2 and MAPKs was induced by Zn-12, and PD98059, a MEK1 inhibitor, significantly suppressed the stimulatory effect of Zn-12 on vascular endothelial cell proliferation. Therefore, it is suggested that Zn-12 activates the FGF-2 pathway via activation of ERK1/2 signaling to stimulate vascular endothelial cell proliferation, although FGF-2-independent mechanisms are also involved in the stimulation. Zn-12 and related compounds may be promising molecular probes to analyze biological systems of vascular endothelial cells.

Graphical abstract: Zn(ii)2,9-dimethyl-1,10-phenanthroline stimulates cultured bovine aortic endothelial cell proliferation

Supplementary files

Article information

Article type
04 Aug 2020
15 Nov 2020
First published
20 Nov 2020
This article is Open Access
Creative Commons BY license

RSC Adv., 2020,10, 42327-42337

Zn(II)2,9-dimethyl-1,10-phenanthroline stimulates cultured bovine aortic endothelial cell proliferation

T. Nakamura, E. Yoshida, T. Hara, T. Fujie, C. Yamamoto, Y. Fujiwara, F. Ogata, N. Kawasaki, R. Takita, M. Uchiyama and T. Kaji, RSC Adv., 2020, 10, 42327 DOI: 10.1039/D0RA06731H

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