Caveolin-1 deficiency decreases atherosclerosis by hampering leukocyte influx into the arterial wall and generating a regulatory T-cell response

Caveolin-1 plays a crucial role in atherosclerosis, which is mainly attributed to its effects on low-density-lipoprotein (LDL) transcytosis. However, caveolin-1 has also been implicated in the regulation of inflammation. We investigated the effects of caveolin-1 deficiency in atherosclerosis with its accompanying changes in plaque- and lymphoid-related immunology and inflammation. Cav1 ^-/-Apoe ^-/- mice exhibited a 15-fold reduction in plaque size with plaques containing fewer macrophages, T cells, and neutrophils. Intravital microscopy revealed 83% less leukocyte adhesion to the vessel wall in Cav1 ^-/-Apoe ^-/- mice, which could be attributed to reduced endothelial chemokine ligand- 2 (CCL-2/MCP-1) and vascular cell adhesion molecule- 1 (VCAM-1) expression. Caveolin-1 deficiency resulted in a 57% increase in regulatory T cells and a 4% decrease in CD4 ⁺ effector T cells in lymphoid organs. Bone marrow transplantations revealed that Cav1 ^-/-Apoe ^-/- mice receiving Cav1 ^+/+Apoe ^-/- or Cav1 ^-/-Apoe ^-/- bone marrow presented 4- to 4.5-fold smaller plaques with no additional phenotypic changes. In contrast, atherosclerosis was not affected in Cav1 ^+/+ Apoe ^-/- recipients receiving Cav1 ^-/-Apoe ^-/- or Cav1 ^+/+ Apoe ^-/- bone marrow. However, the presence of Cav1 ^-/- Apoe ^-/- bone marrow was associated with an anti-inflammatory T-cell profile. Our study reveals that nonhematopoietic caveolin-1 determines plaque size, whereas hematopoietic caveolin-1 regulates lymphoid immune- modulation. However, both are required for phenotypic modulation of plaques.