Hormonal regulation of rat adrenomedullin gene in vasculature.

Abstract

Adrenomedullin (AM), a novel vasodilatory peptide originally isolated from human pheochromocytoma, has subsequently been shown to be expressed in a variety of tissues, such as adrenal gland, lung, heart, kidney, and aorta. To determine whether vascular AM gene expression is under hormonal control, the effects of dexamethasone (DEX) and T3 on AM messenger RNA (mRNA) expression were tested in cultured rat vascular endothelial cells and smooth muscle cells (VSMCs) by Northern blot analysis using polymerase chain reaction-cloned rat AM complementary DNA as a probe. DEX dose and time dependently increased steady-state AM mRNA levels in both endothelial cells and VSMC. T3 modestly induced AM mRNA expression in both cells, whereas rT3, a biologically inactive isomer of T3, failed to affect AM mRNA expression. A glucocorticoid receptor antagonist (RU 38486) blocked DEX-induced AM mRNA expression in both cells, whereas neither estradiol nor testosterone affected AM mRNA expression. Actinomycin D abolished basal as well as stimulated AM mRNA expression by T3, whereas cycloheximide markedly increased steady state mRNA levels (superinduction). The approximate half-lives of basal and stimulated expression of AM mRNA by DEX in VSMC were within 1 h. In contrast, there was little, if any, decay in cycloheximide-induced AM mRNA expression over 6 h. Our study demonstrates that the AM gene expressed by vascular endothelial and smooth muscle cells is similarly regulated by glucocorticoid and possibly by thyroid hormone, and that superinduction of AM mRNA is most likely due to increased mRNA stability.