Vascular injury causes neointimal formation in angiotensin II type 1a receptor knockout mice

Many studies using small-animal models suggest that angiotensin II (Ang II) plays an important role in neointimal formation after vascular injury. In the present study, we examined whether Ang II type 1 receptor (AT(1))-mediated Ang II signaling is indispensable for the development of injury-induced neointimal formation using AT(1a) knockout (KO) mice. Reverse transcriptase-polymerase chain re action analysis revealed that AT(1) mRNA was not detectable in both uninjured and injured carotid arteries of KO mice, whereas the AT(1) gene was expressed in uninjured carotid arteries of wild-type (WT) mice. At 14 days after injury, AT(1) mRNA levels were increased by 1.5-fold in injured arteries of WT mice. Although AT(2) mRNA was not detectable in uninjured arteries, expression of AT(2) gene was induced in both animal groups at 2 weeks after injury. Vascular injury induced neointimal formation in KO mice as well as in WT mice. There were no significant differences between WT and KO mice in the extent of histological findings such as increased cross-sectional areas of the neointima and the media, the number of proliferating smooth muscle cells, and the amount of collagen and fibronectin. Treatment with subpressor doses of Ang II after injury enhanced the growth of neointima in WT mice but not in KO mice. Moreover, treatment with the selective AT(1) antagonist CV-11974 before injury significantly decreased the formation of neointima in only WT mice, whereas treatment with the selective AT(2) antagonist PD-123319 before injury had no effects in both animal groups. These results suggest that AT(1)-mediated Ang II signaling is not essential for the development of neointimal formation, although it may modify it.