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Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote
Janka Kisucka1, Anil K Chauhan, Bing-Qiao Zhao
1Immune Disease Institute, Harvard Medical School, Boston, MA, USA.
Insights
Elevated soluble P-selectin (sP-selectin) directly contributes to cerebrovascular complications, including increased blood-brain barrier permeability and larger stroke infarcts. This biomarker also exacerbates atherosclerosis development in mice.
Area of Science:
- Cardiovascular Science
- Neuroscience
- Immunology
Background:
- Cerebrovascular and cardiovascular diseases pose significant health risks.
- Soluble P-selectin (sP-selectin) is a known biomarker for platelet and endothelial activation, linked to vascular disease risk.
- The direct contribution of sP-selectin to vascular complications remains unclear.
Purpose of the Study:
- To investigate the direct impact of elevated sP-selectin on blood-brain barrier (BBB) function, stroke outcomes, and atherosclerosis.
- To compare the physiological effects in wild-type mice versus genetically modified mice with high sP-selectin levels.
Main Methods:
- Utilized a mouse model (P-sel(DeltaCT/DeltaCT)) engineered to exhibit high plasma sP-selectin levels.
- Assessed blood-brain barrier permeability, behavioral changes, ischemic stroke outcomes (middle cerebral artery occlusion model), and atherosclerosis development (apoE(-/-) background).
Main Results:
- Mice with elevated sP-selectin showed increased BBB permeability, with some exhibiting hemispheric differences.
- These mice displayed altered social behavior, including increased aggression.
- Larger infarct volumes were observed in the middle cerebral artery occlusion model.
- Enhanced susceptibility to atherosclerotic lesion development was noted in both male and female mice on an apoE(-/-) background.
Conclusions:
- Elevated sP-selectin is not merely a biomarker but actively contributes to vascular disease progression.
- High sP-selectin levels directly impact BBB integrity, stroke severity, and atherosclerosis.
- These findings highlight sP-selectin as a potential therapeutic target for cerebrovascular and cardiovascular diseases.
Abstract:
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.
