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Updated: Jul 6, 2026
Murine Model of CD40-activation of B cells
Published on: March 5, 2010
CD40 ligand promotes Mac-1 expression, leukocyte recruitment, and neointima formation after vascular injury
Guohong Li1, John M Sanders, Melissa H Bevard
1Cardiovascular Division, Robert M. Berne Cardiovascular Research Center, University of Virginia Health System, Charlottesville, VA, USA.
Insights
Elevated soluble CD40 ligand (sCD40L) exacerbates neointima formation after vascular injury by promoting platelet and neutrophil activation. Blocking sCD40L reduces inflammation and neointima in an animal model of atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Immunology
- Atherosclerosis Research
Background:
- High soluble CD40 ligand (sCD40L) levels are linked to cardiovascular diseases and predict adverse outcomes.
- Neointima formation, a hallmark of clinical restenosis, is poorly understood at the molecular level.
Purpose of the Study:
- To investigate the role of elevated sCD40L in neointima formation following vascular injury.
- To elucidate the molecular mechanisms by which sCD40L influences neointima development.
Main Methods:
- Utilized an atherogenic mouse model (apoE-/- mice on Western diet) subjected to carotid denudation injury.
- Administered anti-CD40L monoclonal antibody in vivo to block sCD40L activity.
- Assessed inflammatory cell infiltration (neutrophils, monocytes, macrophages) and neointima area.
- Performed in vitro studies using recombinant CD40L to evaluate effects on platelet and neutrophil activation, co-aggregation, and oxidative burst.
Main Results:
- ApoE-/- mice exhibited severe hypercholesterolemia, hyperglycemia, elevated sCD40L, and exaggerated neointima formation post-injury.
- In vivo blockade of sCD40L attenuated neutrophil and monocyte accumulation early and macrophage infiltration late, significantly reducing neointima formation.
- In vitro, recombinant CD40L induced platelet P-selectin and neutrophil Mac-1 expression, promoting platelet-neutrophil co-aggregation and adhesive interactions.
- Recombinant CD40L also stimulated neutrophil oxidative burst and matrix metalloproteinase-9 release.
Conclusions:
- Elevated sCD40L significantly promotes neointima formation after arterial injury in an atherogenic context.
- sCD40L enhances platelet-leukocyte activation, recruitment, and interaction, contributing to vascular remodeling.
- Targeting sCD40L may represent a therapeutic strategy to mitigate restenosis after vascular interventions.
Abstract:
High levels of circulating soluble CD40 ligand (sCD40L) are frequently found in patients with hypercholesterolemia, diabetes, ischemic stroke, or acute coronary syndromes, predicting an increased rate of atherosclerotic plaque rupture and restenosis after coronary/carotid interventions. Clinical restenosis is characterized in part by exaggerated neointima formation, but the underlying mechanism remains incompletely understood. This study investigated the role of elevated sCD40L in neointima formation in response to vascular injury in an atherogenic animal model and explored the molecular mechanisms involved. apoE(-/-) mice fed a Western diet developed severe hypercholesterolemia, significant hyperglycemia, and high levels of plasma sCD40L. Neointima formation after carotid denudation injury was exaggerated in the apoE(-/-) mice. In vivo, blocking CD40L with anti-CD40L monoclonal antibody attenuated the early accumulation of Ly-6G(+) neutrophils and Gr-1(+) monocytes (at 3 days) and the late accumulation of Mac-2(+) macrophages (at 28 days) in the denudated arteries; it also reduced the exaggerated neointima formation at 28 days. In vitro, recombinant CD40L stimulated platelet P-selectin and neutrophil Mac-1 expression and platelet-neutrophil co-aggregation and adhesive interaction. These effects were abrogated by anti-CD40L or anti-Mac-1 monoclonal antibody. Moreover, recombinant CD40L stimulated neutrophil oxidative burst and release of matrix metalloproteinase-9 in vitro. We conclude that elevated sCD40L promotes platelet-leukocyte activation and recruitment and neointima formation after arterial injury, potentially through enhancement of platelet P-selectin and leukocyte Mac-1 expression and oxidative activity.
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