Abstract 507: Dedicator of Cytokinesis 2 Regulates Smooth Muscle Cell Proliferation via p38 Mitogen-Activated Protein Kinase Signaling Pathway

Smooth muscle cell (SMC) proliferation is an important process during vascular development and involved in vascular remodeling of a number of cardiovascular diseases including atherosclerosis, hypertension, and restenosis after angioplasty. However, the underlying mechanisms are not completely understood. In the present study, we identified dedicator of cytokinesis 2 (DOCK2) as one of the factors mediating the SMC proliferation. Knockout of DOCK2 (DOCK2-/-) caused abnormal blood vessel development in yolk sac and hemorrhage in mouse embryos. In addition, dorsal aorta wall structure was disrupted in DOCK2-/- embryos, and the SMC numbers in the dorsal aorta were decreased by 49% compared with wild type (WT). Consistently, proliferating cell nuclear antigen (PCNA)-positive cells in DOCK2-/- dorsal aorta media were much less the WT. These data suggest that the abnormal vascular development in DOCK2-/- embryos was due to the defective SMC proliferation. In vitro, platelet-derived growth factor (PDGF)-BB and serum upregulated DOCK2 along with PCNA expression in SMCs. Knockout or knockdown of DOCK2 by its shRNA inhibited the PDGF-BB-induced PCNA expression while forced expression of DOCK2 induced PCNA expression in SMCs. 5-ethynyl-2'-deoxyuridine (EdU) assay showed that knockdown of DOCK2 blocked PDGF-BB-induced SMC proliferation. Mechanistically, DOCK2 induced SMC proliferation by activating p38 mitogen-activated protein kinase (MAPK). Overexpression of DOCK2 induced while knockdown of DOCK2 inhibited p38 phosphorylation. Blockade of p38 MAPK signaling by its pathway-specific inhibitor diminished DOCK2-induced SMC proliferation. In a rat carotid artery balloon-injury model, knockdown of DOCK2 by adenoviral delivery of its shRNA blocked the injury-induced neointima formation and attenuated the PCNA expression. Furthermore, deletion of DOCK2 blocked ligation-induced neointima formation and PCNA expression in mouse arteries. Taken together, our studies demonstrated that DOCK2 is an important factor regulating SMC proliferation during embryo development as well as vascular remodeling in pathological conditions.