Do ApoB-containing lipoproteins enter and get retained in the arterial wall?

Subendothelial accumulation of apolipoprotein B (ApoB)-containing lipoproteins, such as low-density lipoprotein (LDL) and lipoprotein(a) [Lp(a)], serves as the primary driver of atherosclerotic plaque development.

Receptor-mediated entry and retention

• ApoB-containing lipoproteins cross the vascular endothelium via active, regulated transcytosis mediated by apical receptors scavenger receptor class B type 1 (SR-B1) and activin receptor-like kinase 1 (ALK1).
• Once in the subendothelial space, positive charges (arginine and lysine residues) on the apoB-100 moiety bind electrostatically to negatively charged glycosaminoglycan chains of extracellular matrix proteoglycans. Lp(a) exhibits enhanced retention through additional hydrophobic binding between its apolipoprotein(a) component and the decorin protein core.

Endothelial activation and recruitment

• Retained lipoproteins undergo oxidative modification to form oxidized (oxLDL) and minimally modified (mmLDL) LDL.
• These modified particles act as damage-associated molecular patterns (DAMPs), binding to endothelial scavenger receptors (LOX-1 and CD36) and activating the NF-κB pathway.
• NF-κB activation upregulates cell adhesion molecules (ICAM-1, VCAM-1) and chemokines (MCP-1, M-CSF), promoting monocyte recruitment and migration into the intima.

Foam-cell formation and local inflammation

• Migrated monocytes differentiate into macrophages, which internalize modified lipoproteins through scavenger receptors (CD36 and LOX-1) without feedback inhibition, leading to foam-cell formation.
• Intracellular cholesterol accumulation and crystallization trigger the CD36-TLR4/6 complex, activating the NLRP3 inflammasome and releasing highly inflammatory cytokines (IL-1β and IL-6) that perpetuate local vascular inflammation.

Bottom line

• ApoB-containing lipoproteins actively enter and bind to the arterial extracellular matrix, where their subsequent modification triggers a cascade of endothelial activation, macrophage foam-cell differentiation, and NLRP3 inflammasome-mediated inflammation.