Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis.
Cerebrovascular and cardiovascular diseases are a major cause of morbidity and mortality. Soluble P-selectin (sP-selectin) is a biomarker for platelet/endothelial activation and is considered a risk factor for vascular disease. sP-selectin enhances procoagulant activity by inducing leukocyte-derived microparticle production and promotes activation of leukocyte integrins. However, it is not known whether it directly contributes to vascular complications. We investigated the effect of increased levels of sP-selectin on blood-brain barrier (BBB) function, stroke outcome, and atherosclerosis by comparing wild-type mice with P-sel(DeltaCT/DeltaCT) mice in which the endogenous P-selectin gene was replaced with a mutant that produces abnormally high plasma levels of sP-selectin. P-sel(DeltaCT/DeltaCT) mice presented several abnormalities, including (1) higher BBB permeability, with 25% of the animals showing differential permeability between the right and left hemispheres; (2) altered social behavior with increased aggression; (3) larger infarcts in the middle cerebral artery occlusion ischemic stroke model; and (4) increased susceptibility to atherosclerotic, macrophage-rich lesion development in both male and female mice on the apoE(-/-) genetic background. Thus, elevated sP-selectin is not only a biomarker for vascular disease, but also may contribute directly to atherosclerosis and cerebrovascular complications.
Immune Disease Institute, Harvard Medical School, Boston, MA, USA.
Janka
J
Kisucka
Anil K
AK
Chauhan
Bing-Qiao
BQ
Zhao
Ian S
IS
Patten
Ayce
A
Yesilaltay
Monty
M
Krieger
Denisa D
DD
Wagner
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood* / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002544:Cerebral Infarction / Q000097:blood* / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D019007:P-Selectin / Q000097:blood* / Q000235:genetics; D012995:Solubility
D001057:Apolipoproteins E; D019007:P-Selectin