Vascular Smooth Muscle Cells Contribute to Atherosclerosis Immunity

Abstract

Vascular smooth muscle cells (VSMCs) constitute the major cells in the media layer of arteries, and are critical to maintain the integrity of the arterial wall. They participate in arterial wall remodeling, and play important roles in atherosclerosis throughout all stages of the disease. Studies demonstrate that VSMCs can adopt numerous phenotypes depending on inputs from endothelial cells (ECs) of the intima, resident cells of the adventitia, circulating immune cells, hormones, and plasma lipoproteins. This plasticity allows them to perform multiple tasks in physiology and disease. In this minireview, we focus on a previously underappreciated activity of VSMCs, i.e., their impact on atherosclerosis immunity via formation of artery tertiary lymphoid organs (ATLOs).

Keywords: adventitia; artery tertiary lymphoid organs; atherosclerosis; endothelial cells; intima; vascular smooth muscle cells.

Figure 1

Phenotypes of VSMCs during atherosclerosis progression reveal extraordinary plasticity. ECs and VSMCs in atherosclerotic plaques show activated phenotypes (➊) (3, 4). Some of the VSMCs originate in the media following recruitment into the intima; other VSMCs may be bone marrow-derived or they may originate from myeloid cells in the circulation (➋) (3). A fraction of VSMCs proliferate (➌) (3, 5). VSMCs secrete extracellular matrix components; the pluripotent transcription factor, i.e., Klf4, may play major roles in a process referred to as phenotype switching (➍) (6, 7). In attempts to shield the atherosclerotic plaque from lethal rupture, Oct4 may control a process that has been termed remigration to form a fibrous cap (➎) (, –10). Senescence and apoptosis trigger the generation of additional inflammatory cytokines to form a necrotic core initiating a vicious cycle with lethal clinical consequences during the late stages of the disease (➏) (3, 4, 11).

Figure 2

Vascular smooth muscle cells (VSMC) participate in adventitia immunity during plaque formation. VSMCs sandwiched between atherosclerotic plaques and the adventitia adopt a lymphoid tissue organizer-like phenotype following activation via plaque-derived cues (➊) and subsequently transdifferentiate into LTo-like cells (➋). By means of their proliferative and cytokine-expressing phenotype they affect the restructuring and sculpting of the adventitia including angiogenesis, HEV formation, and lymph vessel neogenesis (➌). Phenotype switching also results in the expression and secretion of lymphorganogenic chemokines, i.e., CXCL13 and CCL21, thereby promoting ATLO formation depicted schematically in the lower part of the graph (➍).