© 1999 American Heart Association, Inc.
Thrombosis |
Altered Vascular Injury Responses in Mice Deficient in Protease-Activated Receptor-1
From Drug Discovery, The R.W. Johnson Pharmaceutical Research Institute, Spring House, Pa.
Correspondence to Bruce P. Damiano, Drug Discovery, R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477. E-mail bdamiano{at}prius.jnj.com
Abstract—Expression of protease-activated receptor-1 (PAR-1), a cell-surface receptor for thrombin, is increased in balloon-injured rat carotid artery and human atherosclerotic tissue. To examine the role of PAR-1 in vascular injury, we compared vascular injury responses in wild-type (WT) and PAR-1–deficient (PAR-1-/-) mice. Arterial injury was induced by inserting a flexible guidewire into the common carotid artery and withdrawing it 6 times with rotation. Bromodeoxyuridine, delivered subcutaneously by osmotic minipump, was used to measure cellular proliferation. Mice were perfusion-fixed at 1, 2, 5, 10, and 14 days after injury. Extensive endothelial damage, mural thrombosis, platelet adherence, and medial smooth muscle cell loss and necrosis were apparent at day 1 in both WT and PAR-1-/- mice. The incidence of thrombosis or platelet deposition in WT and PAR-1-/- mice declined from 100% at day 1 to 25% and 21%, respectively, at 14 days. Endothelial disruption, as assessed by Evan’s blue uptake, was maximum at day 1 and declined by day 14. This apparent endothelial regrowth was similar in WT and PAR-1-/- mice. Significant medial thickening at 14 days after injury was similar in WT (from 22.8±1.7 to 30.7±1.9 µm) and PAR-1-/- (from 23.2±2.1 to 30.5±2.2 µm) mice. Medial area also increased in response to injury but to a lesser extent in PAR-1-/- mice (from 0.0250±0.0044 to 0.0312±0.0047 mm2) than in WT mice (from 0.0266±0.0040 to 0.0398±0.0050 mm2). Neointima was variable and occurred in 6 of 13 WT and 5 of 12 PAR-1-/- mice. However, intimal area tended to be less in PAR-1-/- mice (0.0016±0.0007 mm2) compared with WT mice (0.0082±0.0032 mm2), although this difference did not achieve statistical significance (P=0.06). Cell density was significantly greater in normal carotids from PAR-1-/- (6.4±0.5x103/mm2) compared with WT (4.3±0.8x103/mm2) mice and remained elevated after injury. Vessel and lumen diameters tended to increase in WT mice after injury, whereas vessel diameter was unchanged and lumen diameter actually decreased in PAR-1-/- mice. Cell proliferation in injured carotid arteries was similar in PAR-1-/- and WT mice. These data suggest that PAR-1-/- may play a role in vascular injury responses in this mouse model via possible effects on extracellular matrix regulation.
Key Words: protease-activated receptor • knockout mouse • thrombin • thrombin receptor • cell proliferation
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