Matricellular proteins in atherosclerosis development

Abstract

The extracellular matrix (ECM) is an intricate network composed of various multi-domain macromolecules like collagen, proteoglycans, and fibronectin, etc., that form a structurally stable composite, contributing to the mechanical properties of tissue. However, matricellular proteins are non-structural, secretory extracellular matrix proteins, which modulate various cellular functions via interacting with cell surface receptors, proteases, hormones, and cell-matrix. They play essential roles in maintaining tissue homeostasis by regulating cell differentiation, proliferation, adhesion, migration, and several signal transduction pathways. Matricellular proteins display a broad functionality regulated by their multiple structural domains and their ability to interact with different extracellular substrates and/or cell surface receptors. The expression of these proteins is low in adults, however, gets upregulated following injuries, inflammation, and during tumor growth. The marked elevation in the expression of these proteins during atherosclerosis suggests a positive association between their expression and atherosclerotic lesion formation. The role of matricellular proteins in atherosclerosis development has remained an area of research interest in the last two decades and studies revealed these proteins as important players in governing vascular function, remodeling, and plaque formation. Despite extensive research, many aspects of the matrix protein biology in atherosclerosis are still unknown and future studies are required to investigate whether targeting pathways stimulated by these proteins represent viable therapeutic approaches for patients with atherosclerotic vascular diseases. This review summarizes the characteristics of distinct matricellular proteins, discusses the available literature on the involvement of matrix proteins in the pathogenesis of atherosclerosis and suggests new avenues for future research.

Keywords: Atherosclerosis; Inflammation; Macrophages; Matricellular proteins; Vascular smooth muscle cells.

Figure 1:. Role of matricellular proteins in the development of atherosclerosis.

Matricellular proteins play roles in various stages of atherosclerosis development, which include: 1. Endothelial damage - Damage to endothelial cells induces endothelial cell inflammation and promotes adhesion and transmigration of monocytes across intima. 2. Lipoprotein entry into subendothelial space - Leaky intima promotes the transport of plasma LDL to the subendothelial space, where LDL particles undergo oxidative and acetylated modifications. 3. Leukocyte recruitment- Endothelial cells with increased expression of adhesion molecules release chemo-attractants which attract monocytes and T lymphocytes. 4. Foam cell formation- Monocytes differentiate into macrophages and engulf native and modified LDL and become foam cells. 5. Plaque progression-Contractile VSMCs in the media dedifferentiate into a synthetic state and migrate into the intima and subendothelial space to form a fibrous cap. 6. Necrotic core formation-Accumulation and coalescence of lipids lead to cell apoptosis and necrosis. Failure to remove apoptotic cells results in the formation of lipid-rich necrotic core.

Figure 2:

(A) THBS1 via CD47 activation induces foam cell formation in macrophages. THBS1 binds with CD47 receptors in macrophages, stimulates receptor-independent macropinocytic internalization of native LDL (nLDL) and modified LDL (mLDL), and contributes to foam cell formation. Modulation of THBS1/CD47 signaling may work as therapeutic target for treating atherosclerosis. THBS1 secreted in response to mechanical stress, binds to VSMC integrin αvβ1 which helps in the maturation of the focal adhesion–actin complex, mediating activation of nuclear shuttling of YAP and ultimately leading to neointima formation. THBS1 targeted therapies using THBS1-blocking antibodies or integrin receptor function inhibitors may also serve as a potential therapeutic target for treating atherosclerosis. (B) Differential effects of myeloid cell-Sirpa and -Cd47 deletion on macrophage efferocytosis and atherosclerosis. Loss of Sirpa signaling in macrophages stimulates efferocytosis, reduces cholesterol accumulation, promotes lipid efflux, and suppresses atherosclerosis. Conversely, myeloid cell-Cd47 deletion inhibits efferocytosis, impairs cholesterol efflux, augments cellular inflammation, and promotes plaque formation.

Figure 3:. RSPO2 inhibits lymphangiogenesis and contributes to atherosclerosis development.

RSPO2 via binding to LGR4 receptors on lymphatic endothelial cells (LEC) hinders VEGF-C-stimulated AKT and eNOS activation, leading to impaired NO production and reduces lymphatic vessel formation. It also inhibits activation of the canonical Wnt-β-catenin pathway in LEC in a NO-dependent manner, thus decreasing lymphatic vessel-mediated LDL drainage from the arterial wall and promoting atherosclerosis.