Altered vascular injury responses in mice deficient in protease-activated receptor-1

Expression of protease-activated receptor-1 (PAR-1), a cell-surface recepto r for thrombin, is increased in balloon-injured rat carotid artery and huma n 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 gui dewire into the common carotid artery and withdrawing it 6 times with rotat ion. Bromodeoxyuridine, delivered subcutaneously by osmotic minipump, was u sed to measure cellular proliferation. Mice were perfusion-fixed at 1, 2, 5 , 10, and 14 days after injury. Extensive endothelial damage, mural thrombo sis, platelet adherence, and medial smooth muscle cell loss and necrosis we re apparent at day 1 in both WT and PAR-1(-/-) mice. The incidence of throm bosis or platelet deposition in WT and PAR-1(-/-) mice declined from 100% a t day 1 to 25% and 21%, respectively, at 14 days. Endothelial disruption, a s 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(-/-) mic e. Significant medial thickening at 14 days after injury was similar in WT (from 22.8 +/- 1.7 to 30.7 +/- 1.9 mu m) and PAR-1(-/-) (from 23.2 +/- 2.1 to 30.5 +/- 2.2 mu m) mice. Medial area also increased in response to injur y but to a lesser extent in PAR-1(-/-) mice (from 0.0250 +/- 0.0044 to 0.03 12 +/- 0.0047 mm(2)) than in WT mice (from 0.0266 +/- 0.0040 to 0.0398 +/- 0.0050 mm(2)). Neointima was variable and occurred in 6 of 13 WT and 5 of 1 2 PAR-1(-/-) mice. However, intimal area tended to be less in PAR-1(-/-) mi ce (0.0016 +/- 0.0007 mm(2)) compared with WT mice (0.0082 +/- 0.0032 mm(2) ), although this difference did not achieve statistical significance (P = 0 .06). Cell density was significantly greater in normal carotids from PAR-1( -/-) (6.4 +/- 0.5 x 10(3)/mm(2)) compared with WT (4.3 +/- 0.8 x 10(3)/mm(2 )) mice and remained elevated after injury. Vessel and lumen diameters tend ed to increase in WT mice after injury, whereas vessel diameter was unchang ed and lumen diameter actually decreased in PAR-1(-/-) mice. Cell prolifera tion in injured carotid arteries was similar in PAR-1(-/-) and WT mice. The se data suggest that PAR-1(-/-) may play a role in vascular injury response s in this mouse model via possible effects on extracellular matrix regulati on.