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 Ϫ/Ϫ ) 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 Ϫ/Ϫ mice. The incidence of thrombosis or platelet deposition in WT and PAR-1 Ϫ/Ϫ 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 Ϫ/Ϫ mice. Significant medial thickening at 14 days after injury was similar in WT (from 22.8Ϯ1.7 to 30.7Ϯ1.9 m) and PAR-1 Ϫ/Ϫ (from 23.2Ϯ2.1 to 30.5Ϯ2.2 m) mice. Medial area also increased in response to injury but to a lesser extent in PAR-1 Ϫ/Ϫ mice (from 0.0250Ϯ0.0044 to 0.0312Ϯ0.0047 mm 2 ) than in WT mice (from 0.0266Ϯ0.0040 to 0.0398Ϯ0.0050 mm 2 ). Neointima was variable and occurred in 6 of 13 WT and 5 of 12 PAR-1 Ϫ/Ϫ mice. However, intimal area tended to be less in PAR-1 Ϫ/Ϫ mice (0.0016Ϯ0.0007 mm 2 ) compared with WT mice (0.0082Ϯ0.0032 mm 2 ), although this difference did not achieve statistical significance (Pϭ0.06). Cell density was significantly greater in normal carotids from PAR-1 Ϫ/Ϫ (6.4Ϯ0.5ϫ10 3 /mm 2 ) compared with WT (4.3Ϯ0.8ϫ10 3 /mm 2 ) 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 Ϫ/Ϫ mice. Cell proliferation in injured carotid arteries was similar in PAR-1 Ϫ/Ϫ and WT mice. Key Words: protease-activated receptor Ⅲ knockout mouse Ⅲ thrombin Ⅲ thrombin receptor Ⅲ cell proliferation S everal lines of evidence suggest a significant role for thrombin in vascular injury responses associated with thrombosis, atherosclerosis, and mechanical arterial injury, such as that caused by balloon angioplasty or stent implantation. [1][2][3] Concentrations of thrombin at sites of vascular injury are significantly elevated. For example, 5 hours after balloon injury of the rabbit aorta, thrombin activity was 50 fmol ⅐ min Ϫ1 ⅐ cm Ϫ2 , gradually decreasing to 10 fmol ⅐ min Ϫ1 ⅐ cm Ϫ2 at 24 hours after injury. 4 These levels were sustained for at least 10 days. In human plasma, thrombin concentrations in the vicinity of a thrombus have been estimated to be as high as 140 nmol/L. 5 In addition to evidence for elevated thrombin levels at sites of vascular injury...