Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury

Abstract

Background - To investigate the effect of angiotensin (Ang) II type 1 receptor (AT1) blocker on vascular remodeling and explore the possibility of the involvement of Ang II type 2 receptor (AT2) stimulation in this process, we examined the effects of the selective AT1 blocker valsartan on the vascular injury in wild-type (Agtr2+) and AT2-null (Agtr2-) mice. Methods and Results - Neointima formation and the proliferation of vascular smooth muscle cells (VSMCs) induced by cuff placement on the femoral artery were greater in Agtr2- mice than those in Agtr2+ mice. Treatment of mice with valsartan at a dose of 1 mg · kg-1 · d-1, which did not influence systolic blood pressure, significantly decreased neointima formation and the proliferation of VSMCs, whereas the valsartan was less effective in Agtr2- mice. Moreover, cuff placement increased the expression of monocyte chemoattractant protein-1 (MCP-1); inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β; and infiltration of CD45-positive leukocytes and macrophages in the injured arteries and further enhanced them in Agtr2- mice, suggesting the antagonistic effects of AT1 and AT2 for vascular inflammation. Valsartan attenuated the expression of MCP-1, TNF-α, IL-6, IL-1β, and infiltration of leukocytes and macrophages in the injured arteries; however, these effects of valsartan were less prominent in Agtr2- mice. Conclusions - These results suggest that the stimulation of the AT2 receptor after AT1 blockade is important in the improvement of the inflammatory vascular injury.