© 1999 American Heart Association, Inc.
Original Contribution |
TIMP-4 Is Regulated by Vascular Injury in Rats
From the Hatter Institute (C.M.D., J.R.M.), University College London Hospitals, London; the Departments of Pediatrics (M.W., Y.E.L.) and Pathology (Y.E.S.), Long Island Jewish Medical Centre, the Long Island Campus for the Albert Einstein College of Medicine; and the Department of Chemistry (Q.A.S.), Florida State University.
Correspondence to Clare M. Dollery, MRCP, PhD, Cardiology Department, 4th Floor, Jules Thorn Building, Middlesex Hospital, Mortimer St, London W1N8AA, UK. E-mail c.dollery{at}ucl.ac.uk
Abstract—The role of basement membrane–degrading matrix metalloproteinases (MMPs) in enabling vascular smooth muscle cell migration after vascular injury has been established in several animal models. In contrast, the role of their native inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), has remained unproven despite frequent coregulation of MMPs and TIMPs in other disease states. We have investigated the time course of expression and localization of TIMP-4 in rat carotid arteries 6 hours, 24 hours, 3 days, 7 days, and 14 days after balloon injury by in situ hybridization, immunohistochemistry, and Western blot analysis. TIMP-4 protein was present in the adventitia of injured carotid arteries from 24 hours after injury. At 7 and 14 days after injury, widespread immunostaining for TIMP-4 was observed throughout the neointima, media, and adventitia of injured arteries. Western blot analysis confirmed the quantitative increase in TIMP-4 protein at 7 and 14 days. In situ hybridization detected increased expression of TIMP-4 as early as 24 hours after injury and a marked induction in neointimal cells 7 days after injury. We then studied the effect of TIMP-4 protein on the migration of smooth muscle cells through a matrix-coated membrane in vitro and demonstrated a 53% reduction in invasion of rat vascular smooth muscle cells. These data and the temporal relationship between the upregulation of TIMP-4, its accumulation, and the onset of collagen deposition suggest an important role for TIMP-4 in the proteolytic balance of the vasculature controlling both smooth muscle migration and collagen accumulation in the injured arterial wall.
Key Words: tissue inhibitor • artery • muscle, smooth, vascular • vascular injury
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