Angiotensin II Type 2 Receptor Gene Transfer Downregulates Angiotensin II Type 1a Receptor in Vascular Smooth Muscle Cells

Abstract

Two distinct subtypes of angiotensin (Ang) II receptors, type 1 (AT1) and type 2 (AT2), have been identified. Vascular smooth muscle cells (VSMCs) usually express AT1 receptor. To elucidate the direct effects of the AT2 receptor on the AT1 receptor in VSMCs, we transfected AT2 receptor gene into cultured rat VSMCs. Overexpression of AT2 receptor significantly decreased expression of AT1a receptor at both the mRNA and protein levels in the presence and absence of Ang II in VSMCs. Overexpression of AT2 receptor increased expression of bradykinin and inducible NO in the presence and absence of Ang II in VSMCs. Bradykinin B2 receptor antagonist HOE–140 and NO synthase inhibitor N&ohgr;-nitro-l-arginine methyl ester (L-NAME) inhibited the decreases in AT1a receptor expression by the overexpression of AT2 receptor in VSMCs. l-Arginine augmented the decrease in AT1a receptor expression. Overexpression of AT2 receptor suppressed basal DNA synthesis and proliferation of VSMCs and abolished response of DNA synthesis to Ang II in VSMCs. Our results demonstrate that overexpression of the AT2 receptor downregulates AT1a receptor expression in rat VSMCs in a ligand-independent manner that is mediated by the bradykinin/NO pathway. Downregulation of AT1a receptor is a novel mechanism by which the AT2 receptor regulates growth and metabolism of VSMCs.