Abstract 13233: Critical Role of Smooth Muscle Rac1 In Neointimal Formation After Vascular Injury
Background: Rac1 is a small Rho GTPase, which plays a critical role in cell movement, spreading, proliferation, transformation, and production of reactive oxygen species (ROS). Because oxidative stress and smooth muscle cell (SMC) migration and proliferation are important for vascular remodeling after injury, we hypothesized that SMC Rac1 may play an important role in neointima formation.
Methods and Results: To investigate the role of SMC Rac1 in neointimal formation, we generated global haploinsufficient Rac1 knock out mice (Rac1+/−) as well as haploinsufficient SMC-specific Rac1+/− (smRac1+/−) mice by crossing smMHC-Cre mice with Rac1 flox/flox mice. Four weeks after carotid artery ligation, neointimal formation in Rac1+/− and smRac1+/− mice was substantially reduced compared to wild-type (WT) or Rac1 flox/+ (control) mice (intima area: WT vs. Rac1+/−, 59.6±12.4 vs. 27.7±6.0 × 103 μm2; control vs. smRac1+/−: 50.7±9.8 vs. 14.3±2.4 × 103 μm2). Aortic SMC isolated from smRac1+/− mice exhibited normal actin cytoskeletal architecture and similar migratory and adherent function compared to control SMCs. However, smRac1+/− SMCs showed decreased myosin light chain (MLC) phosphorylation, chemotaxis, and proliferation compared to control SMCs. Furthermore, SMCs from smRac1+/− mice showed decreased phosphorylation of PAK1 and ERK, and reduced ROS production in response to mechanical stretch compared to that of SMCs from control mice.
Conclusion: These findings indicate that SMC Rac1 mediates SMC migration and proliferation via increased oxidative stress and ERK activation, and plays a critical role in neointimal formation after vascular injury. Therapeutic modalities, which target Rac1 in SMCs, therefore, may be beneficial in preventing vascular proliferative diseases.
- © 2010 by American Heart Association, Inc.