Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model

Background - Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown. Methods and Results - We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null ( MEKK1(-/-)) mice. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1(-/-) arteries compared with WT arteries ( 28 +/- 8 versus 65 +/- 17 mu m(2), P < 0.05). There were no differences in the ratios of proliferating cell nuclear antigen ( PCNA) - positive cells to total cells within the arterial wall between WT and MEKK1(-/-) arteries. Proliferation capacity also did not differ between WT and MEKK1(-/-) cultured aortic smooth muscle cells (AoSMCs). In contrast, the number of intimal PCNA-positive cells 7 days after ligation was significantly smaller in MEKK1(-/-) arteries. Three different migration assays revealed that migration and invasion of MEKK1(-/-) AoSMCs were markedly impaired. Addition of full-length MEKK1 restored the migration capacity of MEKK1(-/-) AoSMCs. The number of MEKK1(-/-) AoSMCs showing lamellipodia formation by epithelial growth factor was significantly smaller compared with those of WT SMCs. Furthermore, uPA expression after ligation was markedly decreased in MEKK1(-/-) arteries. Conclusions - MEKK1 is implicated in vascular remodeling after blood-flow cessation by regulating the migration and uPA expression of SMCs. MEKK1 is a potential target for drug development to prevent vascular remodeling.