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 (AT 1 ) blocker on vascular remodeling and explore the possibility of the involvement of Ang II type 2 receptor (AT 2 ) stimulation in this process, we examined the effects of the selective AT 1 blocker valsartan on the vascular injury in wild-type (Agtr2+) and AT 2 -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 AT 1 and AT 2 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 AT 2 receptor after AT 1 blockade is important in the improvement of the inflammatory vascular injury.