Lipid infiltration promotes trans-differentiation of vascular smooth muscle cells into macrophage-like cells in early lesions of human coronary atherosclerosis.

Background: The trans-differentiation of vascular smooth muscle cells (VSMCs) into macrophage-like phenotypes contributes substantially to the advancement of atherosclerotic lesions. However, it remains uncertain whether this trans-differentiation is involved in the early pathogenesis of human coronary atherosclerosis. Given that lipid deposition is a pathological hallmark of early-stage atheroma and that single-cell evidence implicates lipid-processing signatures in VSMC trans-differentiation, it was hypothesized that lipid infiltration critically triggers this process during the early stages of coronary atherosclerosis.

Methods: Clinical information and lipid profiles were collected from 38 heart transplant recipients. Coronary artery specimens were obtained from their explanted hearts and classified as initial lesions, fatty streaks, or advanced lesions. Immunohistochemical (IHC) staining and immunofluorescence (IF) analyses were performed on the tissue samples to assess lipid infiltration, VSMC phenotype, and trans-differentiation.

Results: Lipid infiltration and VSMC phenotype switching were observed at the initial lesion stage. IHC and semi-quantitative analysis showed that with increasing lipid infiltration, the densities of foam cells, fatty acid binding protein 4 (FABP4)⁺ SMCs, CD248⁺ cells, and CD68⁺ cells rose significantly, correlating with lesion severity. Moreover, the density of FABP4⁺ SMCs was positively associated with intimal thickness as well as the densities of CD248⁺ cells, foam cells, and CD68⁺ cells.

Conclusions: Lipid infiltration begins in the early stages of human coronary artery atherosclerotic lesions and may promote trans-differentiation of intimal SMCs into macrophage-like cells, as indicated by expression of the macrophage-associated protein FABP4. These findings provide novel insight into early atherogenesis and may help identify potential targets for timely prevention and intervention in cardiovascular disease.