Danish Moin

Background: It was recently discovered that there is a presence of lymphatic vessels within the adventitial layer of atherosclerotic arteries. Furthermore, it appears that there is an increase in lymphangiogenesis that develops in concurrence with atherosclerotic vessels.¹  In playing key roles in the removal of interstitial fluid, immune cell transport, and the absorption of dietary lipids, any defects in lymphatic function would result in an inability to maintain fluid homeostasis.^1,3  The localization and functionality of lymph vessels suggest that they may maintain a partial influence over the plaque formation and progression that accompanies atherosclerosis. In this, atherosclerosis transforms from a strictly vascular disease to one including lymphatics as well.

Objective: In this narrative review, the mechanisms through which lymphatic dysfunction contributes to the development of atherosclerotic plaques is explored in order to create novel therapies to treat the disease.

Search Methods: An online search was conducted through the PubMed database in order to discover the current research being conducted on the topic (of which there is very little due to the modernity of this approach. The following keywords were used in order to expedite the search: “atherosclerosis,” “lymphatic system,” “cardiovascular disease,” and “lymphatic dysfunction.”

Results: The inflammatory cytokines and oxidative stress that are found within atherosclerotic plaques can negatively affect the morphology of endothelial cell junctions of lymphatics. This is seen in the transformation of permeable, “button-like” junctions into less permeable, “zipper-like” junctions that cause lymph retention within the affected vessels.⁴  The entrapment of immune cells within atherosclerotic plaques due to impaired lymphatic drainage contributes to the persistence of chronic inflammation and increases the risk of plaque destabilization. This inflammatory environment not only accelerates plaque growth but also increases the potential for plaque rupture, thus implicating lymphatic dysfunction as a key component of atherosclerotic complications.¹ Lymphatic vessels also conduct a central role in reverse cholesterol transport (RCT), which is the process by which cholesterol is transported from peripheral tissues back to the liver to be excreted. The induction of lymphangiogenesis through VEGFC administration was shown to both improve lymphatic function as well as alleviate cholesterol buildup through improved RCT rates.^3,5 Apolipoprotein A-I (ApoA-I), which is a major protein component of HDL, enhances cholesterol mobilization through its innate ability to pack large amounts of cholesterol following its interaction with ABCA1 on cell membranes. However, this effect is blunted when lymphatic function is impaired, thus highlighting the dependency of proper lipid clearance on a functional lymphatic system.⁵

Conclusion: The discovery of dysfunctional lymphatic vessels within atherosclerotic arteries has significantly expanded the conceptual framework of atherosclerosis, implicating lymphatic components as active regulators of atherosclerotic disease processes rather than passive bystanders. It is for this reason that future research should focus on human validation and clinical integration of lymphatic-targeted therapies.

Works Cited:

1. Csányi G, Singla B. Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges. Journal of Clinical Medicine. 2019; 8(4):495. https://doi.org/10.3390/jcm8040495
2. Yeo KP, Lim HY, Angeli V. Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis. Cells. 2021; 10(6):1344. https://doi.org/10.3390/cells10061344
3. Aspelund A, Robciuc MR, Karaman S, Makinen T, Alitalo K. Lymphatic System in Cardiovascular Medicine. Circulation Research. 2016;118(3):515-530. https://doi.org/10.1161/circresaha.115.306544
4. Peluzzo AM, Bkhache M, Do LNH, Autieri MV, Liu X. Differential regulation of lymphatic junctional morphology and the potential effects on cardiovascular diseases. Frontiers in Physiology. 2023;14. https://doi.org/10.3389/fphys.2023.1198052
5. Milasan A, Jean G, Dallaire F, et al. Apolipoprotein A-I Modulates Atherosclerosis Through Lymphatic Vessel-Dependent Mechanisms in Mice. Journal of the American Heart Association. 2017;6(9):e006892. https://doi.org/10.1161/JAHA.117.006892