Suppressed smooth muscle proliferation and inflammatory cell invasion after arterial injury in elafin-overexpressing mice.
Elastases degrade the extracellular matrix, releasing growth factors and chemotactic peptides, inducing glycoproteins such as tenascin, and thereby promoting vascular cell proliferation and migration. Administration of serine elastase inhibitors reduces experimentally induced vascular disease. The ability to mount an intrinsic anti-elastase response may, therefore, protect against intimal/medial thickening after vascular injury. To investigate this, we showed that wire-induced endothelial denudation of the carotid artery is associated with transient elevation in elastase activity and confirmed that this is abolished in transgenic mice overexpressing the serine elastase inhibitor, elafin, targeted to the cardiovascular system. Ten days after injury, nontransgenic littermates show vessel enlargement, intimal thickening, increased medial area and cellularity, and 2-fold increase in tenascin. Injured vessels in transgenic mice become enlarged but are otherwise similar to sham-operated controls. Injury-induced vessel wall thickening, which is observed only in nontransgenic mice, is related to foci of neutrophils and macrophages, in addition to smooth muscle cells that fail to stain for alpha-actin and are likely dedifferentiated. Our study therefore suggests that a major determinant of the vascular response to injury is the early transient induction of serine elastase activity, which leads to cellular proliferation and inflammatory cell migration.
Zaidi
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Program in Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario, Canada.
You
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Ciura
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O'Blenes
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Husain
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Rabinovitch
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D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology*; D002342:Carotid Artery, External / Q000473:pathology / Q000502:physiology*; D002455:Cell Division; D004790:Enzyme Induction; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000293:injuries* / Q000473:pathology / Q000502:physiology; D010196:Pancreatic Elastase / Q000096:biosynthesis; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics / Q000502:physiology*
D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D010196:Pancreatic Elastase