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 microm) and PAR-1(-/-) (from 23.2+/-2.1 to 30.5+/-2.2 microm) 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.
Cheung
W M
WM
Drug Discovery, The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
D'Andrea
M R
MR
Andrade-Gordon
P
P
Damiano
B P
BP
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D002339:Carotid Arteries / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000737:chemistry / Q000293:injuries / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000032:analysis / Q000235:genetics*; D013917:Thrombin / Q000502:physiology; D013927:Thrombosis / Q000503:physiopathology; D013997:Time Factors; D017539:Tunica Intima / Q000737:chemistry / Q000293:injuries / Q000473:pathology
D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D013917:Thrombin