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

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 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 injury but to a lesser extent in PAR-1(-/-) mice (from 0.0250 +/- 0.0044 to 0.0312 +/- 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 12 PAR-1(-/-) mice. However, intimal area tended to be less in PAR-1(-/-) mice (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 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.