Paradoxical effects of iron chelation on growth of vascular endothelial cells.

Endothelial cell (EC) and vascular smooth muscle cell (VSMC) interactions play critical roles in restenosis following vascular injury. We examined the effects of intracellular iron chelation on endothelial cell cycle progression and VSMC modulation of endothelial cell growth. A diffusible, lipid-soluble iron chelator that rapidly enters cells, desferri-exochelin 772SM (D-Exo), was studied in human endothelial cells and VSMCs. In both cell types D-Exo reversibly halted cell cycle progression from G0/G1 phase to S phase and from S phase to G2/M phase and increased expression of hypoxia-inducible factor 1alpha (HIF-1alpha). D-Exo increased secretion of vascular endothelial growth factor (VEGF), a downstream target of HIF-1alpha, in VSMCs, but there was no VEGF production in endothelial cells. D-Exo was 25-fold more potent than the lipid-insoluble iron chelator deferoxamine, which does not readily enter cells. Intracellular iron chelation with D-Exo directly inhibits endothelial cell growth but indirectly stimulates endothelial cell growth by increasing VEGF release by VSMCs.