title: Loss of the alpha7 integrin promotes extracellular signal-regulated kinase activation and altered vascular remodeling.
abstract: Vascular smooth muscle cell (VSMC) proliferation and migration are underlying factors in the development and progression of cardiovascular disease. Studies have shown that altered expression of vascular integrins and extracellular matrix proteins may contribute to the vascular remodeling observed after arterial injury and during disease. We have recently shown that loss of the alpha7beta1 integrin results in VSMC hyperplasia. To investigate the cellular mechanisms underlying this phenotype, we have examined changes in cell signaling pathways associated with VSMC proliferation. Several studies have demonstrated the mitogen-activated protein kinase signaling pathway is activated in response to vascular injury and disease. In this study, we show that loss of the alpha7 integrin in VSMCs results in activation of the extracellular signal-regulated kinase and translocation of the activated kinase to the nucleus. Forced expression of the alpha7 integrin or use of the mitogen-activated protein kinase kinase 1 inhibitor U0126 in alpha7 integrin-deficient VSMCs suppressed extracellular signal-regulated kinase activation and restored the differentiated phenotype to alpha7 integrin-null cells in a manner dependent on Ras signaling. Alpha7 integrin-null mice displayed profound vascular remodeling in response to injury with pronounced neointimal formation and reduced vascular compliance. These findings demonstrate that the alpha7beta1 integrin negatively regulates extracellular signal-regulated kinase activation and suggests an important role for this integrin as part of a signaling complex regulating VSMC phenotype switching.
authors: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors: Jennifer V
authors: JV
authors: Welser
authors: Naomi
authors: N
authors: Lange
authors: Cherie A
authors: CA
authors: Singer
authors: Margaret
authors: M
authors: Elorza
authors: Paul
authors: P
authors: Scowen
authors: Kathleen D
authors: KD
authors: Keef
authors: William T
authors: WT
authors: Gerthoffer
authors: Dean J
authors: DJ
authors: Burkin
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039001:Integrin alpha Chains / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; C085725:integrin alpha7; D048049:Extracellular Signal-Regulated MAP Kinases