Inhibition of ERK1/2 phosphorylation: a new strategy to stimulate elastogenesis in the aorta

Haploinsufficiency of elastin leads, in more than half of patients with Williams-Beuren syndrome, to development of supravalvular aortic stenosis and hypertension. Determining mechanisms implicated in elastin synthesis would be of interest to find new elastogenic molecules to treat such a pathology. Here, we analyzed the signaling pathway linking intracellular calcium concentration to elastin regulation to find new molecules able to increase elastin synthesis. Their elastogenic ability was then investigated, in vitro and in vivo, using inhibitors of the highlighted pathway. The Brown Norway rat strain was used here as an arterial elastin-deficient model. Our data indicated that A23187, a calcium ionophore, decreases elastin expression in cultured vascular smooth muscle cells, both transcriptionally and post-transcriptionally. Addition of A23187 induced transient activation of extracellular signal-regulated kinases 1/2, leading to an upregulation of activator protein-1 transcription factors, which correlated with the inhibition of elastin gene transcription. Pretreatment with U0126, an inhibitor of extracellular signal-regulated kinases 1/2 phosphorylation, abolished the inhibition of elastin gene transcription by A23187. In vitro, U0126 increased elastin synthesis and in vivo, 24 hours after an intravenous administration, elastin gene transcription and elastin mRNA levels were increased in the rat aorta. A chronic treatment, diffusing U0126 for 10 weeks, increased aortic elastin content without changing cell number and collagen content. In conclusion, calcium ionophore represses elastin gene transcription via activation of extracellular signal-regulated kinases 1/2 pathway and activator protein-1 transcription factors. Moreover, we provide strong evidence that inhibition of extracellular signal-regulated kinases 1/2 increases elastin synthesis and could thus be suitable for treating vascular pathologies characterized by diminished arterial elastin content.