Platelet, not endothelial, P-selectin is required for neointimal formation after vascular injury.
BACKGROUND
P-selectin blockade significantly inhibits inflammation and neointimal formation after arterial injury; however, the independent roles of platelet and endothelial P-selectins in this process are unknown. In atherosclerosis, both platelet and endothelial cell P-selectins are important. This study was designed to determine whether P-selectin expression on platelet, endothelial, or both surfaces is critical to the inflammatory response and neointimal formation after arterial injury.


RESULTS
Using wild-type (WT) and P-selectin-knockout (Psel(-/-)) mice, we performed bone marrow transplantation to generate chimeric mice that expressed either platelet P-selectin (Plt-Psel) or endothelial P-selectin (EC-Psel). Double injury of the carotid artery was performed in these mice as well as in WT and Psel(-/-) mice. Animals were euthanized 4 or 21 days after arterial injury. Morphometric data showed that there was more neointimal formation in the WT mouse group when compared with the Psel(-/-) mouse group (0.015+/-0.004 vs 0.004+/-0.004 mm2, P<0.001). Further comparison showed significantly less neointimal area in EC-Psel mice (0.006+/-0.004 mm2) compared with Plt-Psel mice (0.011+/-0.005 mm2, P=0.026) and WT mice (0.015+/-0.004 mm2, P=0.001). No significant differences were observed between WT and Plt-Psel mice or between Psel(-/-) and EC-Psel mice. Decreased neointimal formation was accompanied by a reduced inflammatory response, as evidenced by immunostaining of RANTES and MCP-1 4 days after injury.


CONCLUSIONS
Platelet P-selectin expression, but not endothelial P-selectin, plays a crucial role in the development of neointimal formation after arterial injury, and therapeutic strategies targeting leukocyte-platelet interactions could be effective in inhibiting restenosis.
Wang
Kai
K
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA. wangk@ccf.org
Zhou
Xiaorong
X
Zhou
Zhongmin
Z
Mal
Niladri
N
Fan
Liming
L
Zhang
Ming
M
Lincoff
A Michael
AM
Plow
Edward F
EF
Topol
Eric J
EJ
Penn
Marc S
MS
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D020212:Carotid Artery Injuries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006965:Hyperplasia; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D017539:Tunica Intima / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019007:P-Selectin; D010446:Peptide Fragments; C106929:monocyte chemoattractant protein 1 (9-76)