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Atherosclerosis is a progressive disease marked by the accumulation of lipids, inflammatory cells, and extracellular matrix components in the arterial walls, leading to plaque formation and the narrowing of blood vessels. This pathological process can significantly impair blood flow and contribute to a range of cardiovascular diseases, including coronary artery disease (CAD), stroke, and peripheral artery disease. One of the body’s adaptive responses to ischemia (lack of oxygen) caused by atherosclerotic plaque build-up is angiogenesis, the formation of new blood vessels. These new vessels are intended to improve oxygen delivery to the affected tissues. In the context of atherosclerosis, angiogenesis can lead to the development of collateral circulation, a network of small blood vessels that bypasses the obstructed or narrowed artery. While collateral circulation is generally viewed as a protective mechanism to compensate for reduced blood flow, the role of angiogenesis in atherosclerosis is complex [1]. It can be both beneficial in some instances and harmful in others, depending on factors such as plaque characteristics and the nature of the newly formed vessels. This article explores the relationship between angiogenesis, collateral circulation, and atherosclerosis, discussing the potential protective and harmful effects of these processes in cardiovascular disease.

Description

The mechanism of angiogenesis in atherosclerosis

Angiogenesis is the process by which new blood vessels form from pre-existing ones, driven by the activation of endothelial cells that line the blood vessels. In atherosclerosis, angiogenesis is triggered by tissue hypoxia low oxygen levels resulting from the narrowing or blockage of arteries due to atherosclerotic plaques. When blood flow is reduced or obstructed by plaques, the affected tissues signal for the formation of new blood vessels to restore oxygen supply [2].

Several factors contribute to angiogenesis, the most important of which is vascular endothelial growth factor. VEGF is upregulated in response to hypoxia and stimulates endothelial cells to proliferate, migrate, and form new vessels. Other angiogenic factors, such as fibroblast growth factors (FGFs) and angiopoietins, also play roles in the process by promoting endothelial cell survival and stabilizing the newly formed blood vessels. However, the blood vessels that form in response to angiogenesis in atherosclerotic tissue are often abnormal dysfunctional and fragile making the process both beneficial and potentially harmful.

Protective aspects of angiogenesis and collateral circulation

Restoration of blood flow: The most obvious protective aspect of angiogenesis and collateral circulation is its ability to restore blood flow to tissues that have been deprived of oxygen due to narrowed or occluded arteries. In coronary artery disease, for instance, collateral vessels can reduce the severity of ischemia, which may help prevent heart attacks or reduce the frequency of angina. Similarly, in peripheral artery disease, collateral circulation can improve limb function and reduce symptoms of leg pain during walking [3].

Reduced risk of myocardial infarction: Collateral circulation in the coronary arteries may provide an important protective mechanism against myocardial infarction (heart attack) by providing an alternative route for blood flow when a coronary artery is blocked or narrowed. This can help prevent tissue death in the affected part of the heart muscle, reducing the extent of the infarction and improving overall cardiac function.

Harmful aspects of angiogenesis and collateral circulation

Formation of dysfunctional vessels: While angiogenesis aims to improve oxygenation, the new blood vessels that form in response to VEGF and other pro-angiogenic factors are often structurally abnormal. These vessels may be leaky, prone to rupture, or insufficiently mature to carry adequate blood flow [4]. In atherosclerotic plaques, this can contribute to further plaque instability and increase the risk of rupture, which can lead to acute cardiovascular events, such as heart attacks or strokes [5].

Exacerbation of inflammation: Angiogenesis within atherosclerotic plaques is often accompanied by an inflammatory response. Inflammatory cytokines and immune cells, such as macrophages, can promote the expression of angiogenic factors like VEGF. However, these inflammatory processes can also weaken the fibrous cap of the plaque, making it more likely to rupture [6]. Therefore, the angiogenic response that forms collateral circulation may paradoxically contribute to plaque instability and increase the risk of atherothrombosis (the formation of a clot at the site of plaque rupture) [7,8].

Collateral circulation and angiogenesis in acute events: In cases of acute coronary syndrome (ACS), the rapid expansion of collateral vessels may not be sufficient to prevent myocardial infarction if the blockage is sudden or complete. In these situations, the newly formed collateral vessels might be too small or immature to provide an adequate bypass for blood flow, resulting in tissue damage. Furthermore, angiogenesis in response to an acute event may promote the growth of fragile vessels that cannot withstand the mechanical stress of blood flow, potentially leading to further complications such as hemorrhage within the plaque.

Conclusion

Angiogenesis and collateral circulation play complex roles in the progression of atherosclerosis. While angiogenesis can help restore blood flow to ischemic tissues and provide protection against acute cardiovascular events, it can also contribute to plaque instability and the formation of dysfunctional blood vessels. In the context of atherosclerosis, collateral circulation can be both protective and harmful, depending on factors such as the maturity of the new blood vessels, the degree of inflammation, and the characteristics of the plaque. Understanding these processes and developing targeted therapies to modulate angiogenesis holds promise for improving the management of atherosclerosis and its complications, helping to optimize the balance between promoting tissue repair and preventing plaque rupture and thrombosis.

Acknowledgement

None

Conflict of Interest

None

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