CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation.

Area of Science:

• Cardiovascular Biology
• Immunology
• Vascular Biology

Background:

• Hypercholesterolemia induces endothelial dysfunction, leading to a proinflammatory and prothrombogenic microvasculature.
• The CD40 ligand (CD40L) and its receptor CD40 pathway are involved in inflammatory responses and platelet activation.

Purpose of the Study:

• To investigate the role of the CD40/CD40L pathway, specifically T-cell CD40L, in hypercholesterolemia-induced microvascular dysfunction.
• To determine the contribution of CD40/CD40L to leukocyte and platelet adhesion, vasodilation, and oxidative stress in hypercholesterolemia.

Main Methods:

• Utilized intravital microscopy in wild-type, CD40-deficient, CD40L-deficient, and SCID mice on normal or high-cholesterol diets.
• Assessed leukocyte and platelet recruitment, endothelium-dependent vasodilation, and microvascular oxidative stress.
• Employed bone marrow chimeras and T-cell transfer experiments to elucidate cellular origins of CD40/CD40L effects.

Main Results:

• High-cholesterol diet induced increased leukocyte/platelet adhesion and impaired vasodilation in wild-type mice.
• CD40, CD40L, or lymphocyte deficiency attenuated these hypercholesterolemia-induced responses.
• T-cell transfer rescued the hypercholesterolemic phenotype in CD40L-deficient and SCID mice.
• Hypercholesterolemia-induced oxidative stress was abrogated by CD40/CD40L deficiency and restored by T-cell transfer.

Conclusions:

• CD40/CD40L interactions between circulating cells and the vascular wall mediate microvascular dysfunction in hypercholesterolemia.
• T-cell-associated CD40L is a critical mediator of hypercholesterolemia-induced arteriolar and venular dysfunction.
• Targeting the CD40/CD40L pathway may offer therapeutic potential for managing hypercholesterolemia-related vascular complications.