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
Year: 2005
Type: article
Abstract: 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 microm2, 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.
Source: Circulation
Authors: Yan Li, Tetsuo Minamino, Osamu Tsukamoto, Toshiaki Yujiri, Yasunori Shintani, Ken-ichiro Okada, Yoko Nagamachi, Masashi Fujita, Akio Hirata, Shoji Sanada, Hiroshi Asanuma, Seiji Takashima, Masatsugu Hori, Gary L. Johnson, Masafumi Kitakaze
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2167053877