Insulin and Insulin‐Like Growth Factors Induce Expression of Angiotensin Type‐2 Receptor in Vascular‐Smooth‐Muscle Cells

Angiotensin type-2 receptor (AT2) is abundant in fetal tissues, including aorta, and its expression level declines after birth. In the present study, the regulation of its expression was studied in cultured vascular-smooth-muscle cells (VSMC). The maximum number of binding sites of AT2 increased in VSMC after they were cultured without serum in the presence of insulin, which was essential for its expression. AT2 expression was inhibited by treatment with phorbol ester. Northern blot analyses revealed that insulin-dependent expression is due to elevation of mRNA level of AT2. Similar induction was observed when insulin-like growth factor (IGF)-I or IGF-II was used instead of insulin. The study on the dose dependencies of these factors revealed that the induction of AT2 expression was mediated through the activation of IGF-I receptors. The insulin-induced expression of AT2 was detected in the aorta of genetically obese (fa/fa) Zucker rats, which reportedly have approximately tenfold-higher plasma concentrations of insulin than their lean littermates. The insulin-dependence seems characteristic of VSMC, because it was not observed for pheochromocytoma cells or adrenal glands. These results suggest that the expression of AT2 is regulated by at least two mechanisms, that is, IGF-I receptor dependent and IGF-I receptor independent, and that the former may play an important role in the expression of AT2 in VSMC.