Endothelial Dysfunction in Obesity-Induced Inflammation: Molecular Mechanisms and Clinical Implications

Abstract

Obesity is characterized by the excessive deposition of fat that may interfere with the normal metabolic process of the body. It is a chronic condition associated with various metabolic syndromes, whose prevalence is grossly increasing, and affects both children and adults. Accumulation of excessive macronutrients on the adipose tissues promotes the secretion and release of inflammatory mediators, including interleukin-6 (IL-6), interleukin 1β, tumor necrotic factor-α (TNF-α), leptin, and stimulation of monocyte chemoattractant protein-1 (MCP-1), which subsequently reduce the production of adiponectin thereby initiating a proinflammatory state. During obesity, adipose tissue synthesizes and releases a large number of hormones and cytokines that alter the metabolic processes, with a profound influence on endothelial dysfunction, a situation associated with the formation of atherosclerotic plaque. Endothelial cells respond to inflammation and stimulation of MCP-1, which is described as the activation of adhesion molecules leading to proliferation and transmigration of leukocytes, which facilitates their increase in atherogenic and thromboembolic potentials. Endothelial dysfunction forms the cornerstone of this discussion, as it has been considered as the initiator in the progression of cardiovascular diseases in obesity. Overexpression of proinflammatory cytokines with subsequent reduction of anti-inflammatory markers in obesity, is considered to be the link between obesity-induced inflammation and endothelial dysfunction. Inhibition of inflammatory mechanisms and management and control of obesity can assist in reducing the risks associated with cardiovascular complications.

Keywords: adipose tissue; atherosclerosis; endothelial dysfunction; inflammation; obesity.

Conflict of interest statement

The authors declared no conflict of interest.

Figures

Figure 1

Obesity, inflammation, and related metabolic syndrome. The linking mechanisms: Obesity results from the accumulation of excessive macronutrients in the adipose tissues, which stimulate them to release inflammatory mediators such as TNF-α and IL-6, and the subsequent decreased production of adiponectin, leading to the predisposition of the endothelium to a proinflammatory state gearing to endothelial dysfunction. In addition, excessive accumulation of free fatty acids also activates proinflammatory serine kinase cascades, such as IkB kinase, Toll-like receptor, and c-Jun N-terminal kinase, which in turn facilitate adipose tissue to release IL-6 that triggers hepatocytes to produce and secrete CRP. All these are associated with the development of cardiovascular diseases, including atherosclerosis and other metabolic syndromes, as well as non-cardiovascular diseases such as renal diseases. A decreased level of adiponectin is also characterized by impaired fasting glucose, coronary artery calcification, and stroke. Hypoxia is described to be the etiology of necrosis and macrophage infiltration into adipose tissue, leading to overproduction of proinflammatory mediators [15].

Figure 2

Important functions of endothelial cells: Vascular endothelium (VE) regulates vascular homeostasis through maintaining a delicate balance between the secretion of vasodilators and vasoconstrictors. It synthesizes a series of bioactive substances that moderate vascular tone, control permeability, regulate proliferation and migration of smooth muscle cells, decrease leucocyte migration, and regulate platelet adhesion and aggregation. VE also controls cellular adhesion, vascular inflammation, and angiogenesis [5].

Figure 3

Mechanisms of endothelial cell (ECs) dysfunction associated with inflammation. Inflammation leads to an imbalance between proinflammatory and procoagulant, and anti-inflammatory and anticoagulant properties of the endothelium, thus contributing to disturbance of the hemostatic system. Activated or injured ECs mostly secrete procoagulant or antifibrinolytic components, resulting in the subsequent reduction in the expression of anticoagulant and profibrinolytic components. Additionally, activated ECs can express other factors such as TF and adhesion molecules, which have an important role in mediating the interaction of neutrophils and platelets with endothelium, further promoting the inflammatory and hemostatic responses. These disturbances shift the function of ECs from an anticoagulant, anti-inflammatory, and vasodilatory state to a proinflammatory and procoagulant state [49,50].

Figure 4

Common mediators of inflammation associated with the disturbance of the fibrinolytic system: The main mediators of inflammation-induced activation of the hemostatic system, particularly the proinflammatory cytokines, include tumor necrotic factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), which trigger the disturbances of the hemostatic system in different mechanisms, including platelet activation, TF-mediated activation of coagulation cascade, impaired function of anticoagulant pathways and fibrinolytic activities, and endothelial cell dysfunction [50].

Figure 5

Monocyte chemoattractant protein-1 (MCP-1) contributions to endothelial dysfunction during atherosclerosis. Damage on the vascular endothelium leads to the secretion of cytokines and chemokines and the expression of adhesion molecules by the injured endothelium. Leucocytes from the blood are attracted to the site of injury by chemokines, specifically the MCP-1. Initially, monocytes are attached to the endothelial lumen through molecular interactions with adhesion molecules. They transmigrate to the subendothelium, differentiate, and mature to macrophages that release cytokines. Once there are elevated levels of low-density lipoprotein (LDL) and cholesterol, the LDL-c penetrates and infiltrates the subendothelium, and oxidized to ox-LDL mediated by reactive oxidative species (ROS) and is retained in the intima. This results in the activation of endothelium leading to the transmigrations and proliferation of leukocytes (macrophages and T-lymphocytes). The macrophages then take up accumulated ox- LDL-c resulting forming cells and atherogenesis while T-lymphocytes differentiate to T-helper cells. These processes are associated with the secretion of proinflammatory cytokines, which combine with other growth factors to stimulate smooth muscle cells proliferation and migration into the sub-endothelial space (Figure 5). This indicates a fundamental stage in responding to vascular injury and the formation of a fibrous cap with the increased extracellular matrix, causing the thickening of the intima with the subsequent formation of atherosclerotic plaque.