Activation of the D 4 dopamine receptor attenuates proliferation and migration of vascular smooth muscle cells through downregulation of at 1a receptor expression

Abstract

Angiotensin (Ang) II has an important role in the vascular smooth muscle cell (VSMC) proliferation and migration and subsequently in the development of vascular diseases, whereas dopamine has the opposite effect. Previous studies have shown an interaction between dopamine and AT1 receptors in the kidney. The dopamine D4 receptor is expressed in arteries and has an inhibitory effect on VSMC proliferation. We hypothesized that the D4 receptor, through its interaction with the AT 1a receptor, may have an inhibitory effect on Ang II-mediated VSMC proliferation and migration, which could have a pivotal role in hypertension-induced vascular remodeling. In the current study, we found that Ang II markedly induced the proliferation and migration of A10 cells, which was inhibited by the D4 receptor agonist PD168077. The activation of the D4 receptor by PD168077 inhibited AT1a receptor expression in a concentration- and time-dependent manner. These effects were attenuated by silencing the D4 receptor with a D 4 receptor-targeting small interfering RNA. The D4 receptor-mediated inhibition of AT1 receptor function involved protein kinase A (PKA). The activation of the D4 receptor by PD168077 increased PKA activity in A10 cells, and the presence of a PKA inhibitor (PKA inhibitor 14-22, 10 -7 mol l -1 per 24 h) blocked the inhibitory effect of the D 4 receptor on AT 1 receptor expression and function. The inhibitory effect of the D 4 receptor on AT 1 receptor expression and function was preserved in VSMCs (primary culture) from spontaneously hypertensive rats relative to VSMCs from Wistar-Kyoto rats. In conclusion, our data provide insight into the regulatory role of the D4 receptor on AT1a receptor expression and function in VSMCs and suggest that targeting the action of the D4 receptor may represent an effective therapeutic approach for the treatment of cardiovascular diseases.