Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review

Abstract

The concept of vulnerable carotid plaques is pivotal in understanding the pathophysiology of ischemic stroke secondary to large-artery atherosclerosis. In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis; and plaque rupture. Recognizing these macroscopic characteristics is crucial for estimating the risk of cerebrovascular events, also in the case of non-significant (less than 50%) stenosis. Inflammatory biomarkers, such as cytokines and adhesion molecules, lipid-related markers like oxidized low-density lipoprotein (LDL), and proteolytic enzymes capable of degrading extracellular matrix components are among the key molecules that are scrutinized for their associative roles in plaque instability. Through their quantification and evaluation, these biomarkers reveal intricate molecular cross-talk governing plaque inflammation, rupture potential, and thrombogenicity. The current evidence demonstrates that plaque vulnerability phenotypes are multiple and heterogeneous and are associated with many highly complex molecular pathways that determine the activation of an immune-mediated cascade that culminates in thromboinflammation. This narrative review provides a comprehensive analysis of the current knowledge on molecular biomarkers expressed by symptomatic carotid plaques. It explores the association of these biomarkers with the structural and compositional attributes that characterize vulnerable plaques.

Keywords: carotid plaque; inflammation; stroke; vulnerability.

Figure 1

The role of macrophage activation and polarization in plaque vulnerability. The presence of antioxidant enzymes in Mox macrophages, stemming from the accumulation of oxidized phospholipids, confers them an anti-inflammatory function. The polarization of macrophages into M1 or M2 phenotypes plays a crucial role in determining plaque vulnerability. Initially, M2 macrophages predominate in lesions during the early stages of atherosclerotic disease. However, as the disease progresses, there is a shift towards a predominance of M1 cells, heightening the risk of plaque rupture and cerebral complications. Furthermore, M1 macrophages are primarily located in the plaque’s shoulder and necrotic core, while M2 macrophages tend to infiltrate areas near newly formed blood vessels. Macrophages exhibit plasticity in their polarization in response to environmental stimuli. Polarization can shift phenotypes from M1 to M2 in response to IL-4, and vice versa following induction by lipopolysaccharide and IFN-g. The balance between M1 and M2 phenotypes is a dynamic determinant of atherosclerotic plaque vulnerability and the likelihood of acute cerebrovascular events (Created with BioRender.com).

Figure 2

Plaque rupture and thrombosis. Low shear stress triggers the activation of endothelial cells and leukocytes, leading to the upregulation of proinflammatory processes that increase the vulnerability of the lesions. The rupture of the plaque results in compromised endothelial integrity, which is the primary determinant of vascular tone, inflammation activation, and the diffusion of molecules into the subendothelial layer. Upon endothelial damage, platelets adhere to the vascular wall, initiating the formation of a platelet-rich thrombus through the interaction between the platelet glycoprotein (GP) Ibα receptor and von Willebrand factor (vWF), expressed by the injured endothelium. In addition, the GPIbα receptor recruits circulating leukocytes by binding integrins and P-selectin, thereby perpetuating the inflammatory cascade (Created with BioRender.com).

Figure 3

Proinflammatory cytokines such as IFN-γ, TNF-α, and IL-1β promote apoptosis in macrophages and smooth muscle cells, leading to the thinning of the fibrous cap. This thinning allows macrophages to infiltrate the fibrous cap, where they release inflammatory cytokines and MMPs, significantly contributing to the weakening and eventual rupture of the atherosclerotic plaque. The necrosis of the vulnerable plaque occurs due to a combination of macrophage death and impaired phagocytic clearance of apoptotic cells, thereby hastening or triggering plaque disruption through the secretion of inflammatory cytokines and matrix proteases (Created with BioRender.com).

Figure 4

Neovascularization in vulnerable plaque. Pathological angiogenesis consistently accompanies the development of atherosclerotic plaques, with its progression correlated to a gradient of VEGF that triggers endothelial cell growth from pre-existing adventitial vasa vasorum. Neovascularization in vulnerable plaques demonstrates immaturity, irregularity, and fragility due to compromised structural integrity. These vessels exhibit a discontinuous basement membrane and a low number of tight junctions between endothelial cells. These immature vessels have limited pericyte coverage and are susceptible to the leakage of circulating cells, which can lead to intraplaque hemorrhage (Created with BioRender.com).