Abstract 1169: Critical Role of Leukocyte ROCK1 in Mediating Neointimal Formation Following Vascular Injury
Background - Rho kinase (ROCK) has been implicated in vascular inflammation, remodeling, and atherosclerosis. However, the tissue- and isoform-specific roles of ROCKs in mediating these processes are not known.
Methods and Results - To determine the role of ROCKs following vascular injury, we ligated the left common carotid artery in WT, ROCK1+/−, and ROCK2+/− mice. Four weeks after carotid ligation, the neointimal areas were decreased in ROCK1+/− (6,900 ± 3,800 μm2, P < 0.05), but not in ROCK2+/− mice (31,200 ± 8,500 μm2, P = NS), compared to that of WT mice (26,800 ± 5,600 μm2). This correlated with substantial decreases in vascular ROCK activity, neointimal proliferation, proinflammatory adhesion molecules, and leukocyte infiltration in ROCK1+/− mice. Indeed, neutrophil recruitment into the peritoneal cavity after intraperitoneal injection of thioglycollate was reduced in ROCK1+/− mice (7.0 ± 0.3 x 106/ml, P < 0.01) compared to that in WT mice (13.9 ± 0.8 x 106/ml), U937-LAM monocyte accumulation on TNFα-stimulated endothelial cells (EC) from ROCK1+/− mice was 2.5-fold lower than that from WT mice, and thrombin-induced increases in ROCK activity and ICAM-1 and VCAM-1 expressions were impaired in EC from ROCK1+/− mice. Furthermore, in vascular smooth muscle cells from ROCK1+/− mice, PDGF-induced increases in ROCK activity and migration, but not proliferation, were reduced. To determine the role of leukocyte ROCK1 in this process, we transplanted the bone marrow (BM) from donor WT into recipient irradiated WT mice, from WT into irradiated ROCK1+/− mice, and from ROCK1+/− into irradiated WT mice. Transplantation with BM from ROCK1+/− into WT mice resulted in reduced neointimal formation and leukocyte infiltration, while transplantation with BM from WT into ROCK1+/− mice had no substantial effect on them.
Conclusion - These findings indicate that ROCK1, but not ROCK2, mediates leukocyte recruitment and neointimal formation following vascular injury and suggest that leukocyte ROCK1 may be an important therapeutic target in vascular inflammatory and proliferative diseases.