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Atherosclerosis is a chronic cardiovascular disease characterized by the gradual buildup of fatty deposits, inflammatory cells, and fibrous tissue within the arterial walls, leading to the narrowing and stiffening of the arteries. This condition is a major contributor to cardiovascular events such as heart attacks, strokes, and peripheral artery disease. Endothelial dysfunction, a state in which the endothelial cells lining the blood vessels lose their normal properties and functions, plays a central role in the development and progression of atherosclerosis. One of the key processes linked to endothelial dysfunction in atherosclerosis is angiogenesis, the formation of new blood vessels. Although angiogenesis is often considered a reparative response to tissue hypoxia, it can have both beneficial and detrimental effects within atherosclerotic plaques. Understanding the intricate relationship between endothelial dysfunction and angiogenesis is critical to unraveling the pathogenesis of atherosclerosis and developing effective therapeutic strategies [1].

Description

Endothelial dysfunction and its role in atherosclerosis

The endothelium is a monolayer of cells that lines the interior surface of blood vessels, acting as a barrier between the blood and the underlying tissues. It plays an essential role in maintaining vascular homeostasis by regulating blood flow, vascular tone, and coagulation, as well as by mediating inflammatory responses and tissue repair processes. In healthy blood vessels, the endothelium produces vasodilators such as nitric oxide (NO), which helps maintain vascular tone and prevent excessive platelet aggregation. It also limits the adhesion of leukocytes and monocytes to the vessel wall, thus preventing inflammation [2].

Endothelial dysfunction refers to the loss of these normal endothelial functions and is often triggered by risk factors such as high blood pressure, hyperlipidemia, smoking, diabetes, and chronic inflammation. When endothelial dysfunction occurs, the production of vasodilators like nitric oxide is reduced, leading to impaired blood flow and increased vascular resistance. Moreover, the endothelium becomes more permeable to lipids and inflammatory cells, which can infiltrate the arterial wall and initiate the formation of atherosclerotic plaques.

In the context of atherosclerosis, endothelial dysfunction is a critical early event that promotes the development of plaques. Dysfunctional endothelial cells express increased levels of adhesion molecules, which facilitate the recruitment of inflammatory cells (particularly monocytes) to the site of injury. These cells, in turn, release pro-inflammatory cytokines and growth factors that contribute to plaque formation and progression [3].

The role of angiogenesis in atherosclerosis

Angiogenesis, the process of new blood vessel formation from existing vessels, is a physiological response to conditions such as hypoxia, inflammation, and tissue injury. In atherosclerosis, angiogenesis occurs as a result of the growing metabolic demands of developing plaques. As the plaque enlarges, its core may become hypoxic (lacking sufficient oxygen) because of limited blood supply. This hypoxia triggers the secretion of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and angiopoietins, which stimulate endothelial cells to proliferate, migrate, and form new blood vessels within the plaque [4].

While angiogenesis can be beneficial in certain contexts, such as restoring oxygen supply to ischemic tissues, the process within atherosclerotic plaques can have a more complex role. The newly formed blood vessels within plaques are often structurally abnormal, with impaired endothelial cell function and increased permeability. These immature vessels are more prone to rupture, which can lead to plaque destabilization and acute cardiovascular events like heart attacks or strokes.

In atherosclerotic plaques, angiogenesis contributes to a cycle of inflammation and plaque expansion. The newly formed vessels bring additional inflammatory cells, such as macrophages and T-cells, which further fuel the inflammatory process within the plaque. This cycle can result in the formation of larger, more unstable plaques that are more prone to rupture. As the plaque grows and new blood vessels form, the potential for thrombus formation increases, which is a key event in the progression of cardiovascular diseases [5].

Interplay between endothelial dysfunction and angiogenesis in atherosclerosis

The relationship between endothelial dysfunction and angiogenesis in atherosclerosis is intricate and interdependent. Endothelial dysfunction creates an environment that promotes inflammation and the accumulation of lipid-rich plaques in the arterial wall. As the plaques grow, they can become hypoxic, triggering angiogenesis as a compensatory mechanism to restore oxygenation [6]. However, the abnormal endothelial cells that form these new blood vessels are dysfunctional themselves, contributing to further destabilization of the plaque.

The dysfunctional endothelial cells also contribute to the formation of leaky blood vessels, which exacerbate the inflammatory environment within the plaque by allowing the infiltration of inflammatory cells, lipids, and other substances. This leaky vasculature within the plaque leads to the accumulation of additional inflammatory mediators, which, in turn, stimulate further angiogenesis, creating a vicious cycle of endothelial dysfunction and plaque progression. Ultimately, this cascade of events can destabilize the plaque, making it more likely to rupture and cause a sudden, life-threatening vascular event [7,8].

Conclusion

Endothelial dysfunction and angiogenesis are central to the pathogenesis of atherosclerosis. Endothelial dysfunction initiates the inflammatory processes that underlie plaque formation, while angiogenesis attempts to restore blood supply to growing plaques. However, the angiogenic response in atherosclerotic plaques often leads to the formation of fragile, leaky blood vessels that destabilize the plaque and increase the risk of rupture. Understanding the complex molecular pathways involved in endothelial dysfunction and angiogenesis is essential for developing targeted therapeutic strategies to treat atherosclerosis and prevent its associated cardiovascular events. By modulating these processes, we can improve plaque stability and reduce the burden of atherosclerosis-related cardiovascular diseases.

Acknowledgement

None

Conflict of Interest

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References

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