Crosstalk Between Macrophages and Vascular Smooth Muscle Cells in Atherosclerotic Plaque Stability

Abstract

Most acute cardiovascular events are due to plaque rupture, with atheromas containing large necrotic cores and thin fibrous caps being more susceptible to rupture and lesions with small necrotic cores and thick fibrous caps being more protected from rupture. Atherosclerotic plaques are comprised various extracellular matrix proteins, modified lipoprotein particles, and cells of different origins, that is, vascular cells and leukocytes. Although much has been revealed about the mechanisms that lead to plaque instability, several key areas remain incompletely understood. This In-Focus Review highlights processes related to cellular crosstalk and the role of the tissue microenvironment in determining cell function and plaque stability. Recent advances highlight critical underpinnings of atherosclerotic plaque vulnerability, particularly impairments in the ability of macrophages to clear dead cells and phenotypic switching of vascular smooth muscle cells. However, these processes do not occur in isolation, as crosstalk between macrophages and vascular smooth muscle cells and interactions with their surrounding microenvironment play a significant role in determining plaque stability. Understanding these aspects of cellular crosstalk within an atherosclerotic plaque may shed light on how to modify cell behavior and identify novel approaches to transform rupture-prone atheromas into stable lesions.

Keywords: atherosclerosis; extracellular matrix; lipoproteins; macrophages; muscle cells.

Figure 1.. Reciprocal Crosstalk between Macrophages and vSMCs.

Macrophages clearing dead cells produce pro-resolving mediators, such as IL-10, TGFβ, and SPMs. These in turn cause vSMCs to differentiate and deposit ECM, leading to thicker fibrous caps. However, when efferocytosis is impaired, macrophages release pro-inflammatory mediators, such as TNFα, IL-1β, and IL-6 that cause vSMC de-differentiation, ECM degradation, and fibrous cap thinning. These functions are reciprocal and can lead to either plaque stability or rupture-prone atheromas.

Figure 2.. Crosstalk Between Macrophages and vSMCs in Atherosclerosis.

(Left) In stable atherosclerosis, lesional macrophages clearing apoptotic cells produce TGFβ, IL-10, and SPMs. These pro-resolving molecules bind to receptors present on the surface of vSMCs that drive Myocardin/SRF binding to CArG boxes, which promote the expression of genes associated with vSMC quiescence. This can be further enhanced by the interaction between vSMCs and the surrounding ECM through integrins α1β1, α2β1, α3β1, and α7β1. (Right) Plaques vulnerable to rupture contain macrophages with impaired efferocytosis, which leads to the secretion of the proinflammatory cytokines TNFα, IL-1β, and IL-6. These bind to their cognate receptors in vSMCs and downregulate Myocardin expression. Inflammatory cytokines also stimulate the association of KLF4 to G/C elements that prevent SRF binding to CArG boxes. Interactions between vSMCs and the ECM proteins fibronectin, fibrinogen, and vitronectin cause NFκB and NFAT activation and promotes the expression of MMPs and inflammatory genes.