Submitted October 28, 2008
Accepted March 27, 2009
Elevated levels of soluble P-selectin in mice alter blood brain barrier function, exacerbate stroke and promote atherosclerosis
Janka Kisucka, Anil K. Chauhan, Bing-Qiao Zhao, Ian S. Patten, Ayce Yesilaltay, Monty Krieger, and Denisa D. Wagner*
Immune Disease Institute, Harvard Medical School, Boston, MA, United States
Department of Pathology, Harvard Medical School, Boston, MA, United States
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
* Corresponding author; email: wagner{at}idi.harvard.edu.
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 pro-coagulant 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 to P-sel
CT/CT mice in which the endogenous P-selectin gene was replaced with a mutant that produces abnormally high plasma levels of sP-selectin. P-selCT/CT mice presented a number of 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, microphage-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 may directly contribute to atherosclerosis and cerebrovascular complications.
