Abstract 1150: Angiotensin II Type1 Receptor Blocker Inhibits Neointima Formation by Inhibiting Both Smooth Muscle Cell Accumulation and Migration of Circulating Smooth Muscle-like Progenitor Cells
It has been shown that angiotensinII receptor blocker (ARB) has an inhibitory effect on neointima formation. Bone marrow-derived mononuclear cells (BM-MNCs) which express angiotensinII (AngII) type 1 receptor (AT1R) have been shown to give rise to smooth muscle(SM) like cells at injured vascular walls. However, the role of AngII in the process of BM-MNC incorporation to neointimal formation is little known. Human peripheral blood mononuclear cells (PB-MNCs) were cultured in the presence of PDGF-BB and basic FGF. Immunohistochemistry and RT-PCR revealed that PB-MNCs gave rise to SM-like cells. Immunohistochemistry revealed that αSMA, SM1 and SMemb become positive in PB-MNC derived SM-like cells. RT-PCR confirmed the expression of αSMA, SMemb and AT1R mRNA in PB-MNC derived SM- like cells. The number of SM-like progenitor cells were increased by AngII, and this was blocked by an ARB CV-11974(αSMA+cell/ HPF: 32.6±3.3, 23.4±2.3 vs. 19.0±2.0, P<0.001). CV-11974 alone further decreased the number of circulating SM-like progenitor cells (13.8±2.1 vs.19.0±2.0, P<0.001). Next, we examined the effects of AngII and ARB on in vivo wire injury model of mouse femoral artery. BM transplantation was performed from EGFP mice to irradiated WT mice. At 4wks we inserted a guide wire into the left femoral artery of BM transplanted mice. Then AngII(100 ng/ kg/ min, n=5), CV-11974 (1 mg/ kg/ min, n=5) or both (n=5) were infused using osmotic-mini-pumps for 4wks. AngII increased while CV-11974 decreased neointima formation compared to control none treatment mice(Intima/ Media ratio: 1.5±0.3, 0.7±0.1, 1.4±0.4 vs.1.1±0.1, p<0.05). The number of GFP+SM1+cells in neointima were increased in AngII treated mice and both cells types were decreased in CV-11974 co-treated mice. Circulating MNCs, transforming to SM-like cells, contributed to the neointima formation in wire injured arteries. The neointima formation was promoted by AngII, and this was reduced by ARB by inhibiting BM-derived SM-like progenitor cell accumulation. These findings suggest that circulating BM derived SM-like progenitor cells play an important role in the neointima formation, and that in this process the AngII-AT1R system plays a significant role.