Introduction. Atherosclerosis is an accumulation of immune cells due to CCR7-mediated chemotaxis as a result of LDL buildup in the intimal layers of endothelial cells. Atherosclerosis is a major cause of cardiovascular diseases with increased risks of ischemic stroke, peripheral arterial disease, and myocardial infarctions.1,2 Researchers found the involvement of the CCR7 receptor in plaque formation with a positive correlation and upregulation of VEGF-C, a key player in lymphangiogenesis and the egress of immune cell trafficking. This highlights the potential use of the CCR7-CCL19/CCL21 axis in the treatment of atherosclerotic lesions. Methods. Human iliac arteries were biopsied and grouped into atherosclerotic and non-atherosclerotic groups to show CCR7/VEGF-C involvement within the intima-media complex from Grzegorek et al. study.3 Nossent et al. assessed the CCR7 axis in arteriogenesis with two gene expression profiles of mice, good responding-C57BL/6 and poor responding-BALB/c, to compare blood flow recovery in CCR7-/-/LDLR-/- mice and CCR7-/- mice following hindlimb ischemia.4 Karlsen et al. examined the downstream effects of inducing lymphangiogenesis with overexpressed K14-VEGF-C (keratin-14 vascular endothelial growth factor-C) transgenic mice in skin co-stained with LYVE-1 (lymph vessel endothelial hyaluronan receptor-1) and CD31 to assess lymphangiogenesis and enhanced production of CCL21.5 In Milasan et al. study, Ldlr−/− mice and control mice were injected with VEGF-C 152s for 4 weeks, followed by 8 weeks of high-fat diet, accelerating atherosclerosis, followed by 4 weeks of chow diet to stop plaque growth. Lymphatic function was assessed with harvesting skin-draining lymph nodes and Cytometric Bead Array kits.6 Results. VEGF-C and LYVE-1 were correlated with CCR7 expression associating VEGF-C’s involvement in expanding the lymphatic network in atherosclerotic iliac arteries.3 Measuring blood flow recovery indicated that C57BL/6 mice displayed an upregulation of CCR7 receptors after ischemia, associating CCR7 in arteriogenesis.4 Investigators utilizing K14-VEGF-C mice demonstrated the upregulation of CCL21 in LYVE-1+ initial lymphatics in the transgenic mice versus wildtype, implicating the CCR7 axis as a potential downstream effect of inducing lymphangiogenesis.5 Milasan et al. demonstrated plaque buildup was limited in the Ldlr−/− mice after early treatment with VEGF-C 152s due to downregulation of MCP-1, which restrained macrophage accumulation and induced constant expression of VEGFR-3 on lymphatic endothelial cells.6 Conclusion. The CCR7 axis is implicated in the progression of atherosclerotic plaques. Research has shown positive correlations between CCR7 and VEGF-C, a critical component in VEGFR-3 signaling for lymphangiogenesis. This indicates a potential therapeutic target with VEGF-C to modulate disease progression and increase the immune cell efflux.
- Cardiovascular diseases (CVDs). World Health Organization. https://www.who.int/cardiovascular_diseases/en/. Published September 26, 2018. Accessed February 25, 2019.
- Thanassoulis, G. and Afshar, M. (2017). Atherosclerosis – Cardiovascular Disorders – MSD Manual Professional Edition. [online] MSD Manual Professional Edition. Available at: https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis#v31786549 [Accessed 20 Feb. 2019].
- Grzegorek I, Drozdz K, Chmielewska M, et al. Arterial Wall Lymphangiogenesis Is Increased in the Human Iliac Atherosclerotic Arteries: Involvement of CCR7 Receptor. Lymphatic Research and Biology. 2014;12(4):222-231. doi:10.1089/lrb.2013.0048
- Nossent AY, Bastiaansen AJNM, Peters EAB, et al. CCR7‐CCL19/CCL21 Axis is Essential for Effective Arteriogenesis in a Murine Model of Hindlimb Ischemia. Journal of the American Heart Association. 2017;6(3). doi:10.1161/jaha.116.005281
- Karlsen TV, Reikvam T, Tofteberg A, et al. Lymphangiogenesis Facilitates Initial Lymph Formation and Enhances the Dendritic Cell Mobilizing Chemokine CCL21 Without Affecting Migration. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37(11):2128-2135. doi:10.1161/atvbaha.117.309883
- Milasan A, Smaani A, Martel C. Early Rescue of Lymphatic Function Limits Atherosclerosis Progression in Ldlr−/− Mice. Atherosclerosis Supplements. 2019;32:18. doi:10.1016/j.atherosclerosissup.2019.04.054