CCR7-Mediated Chemotaxis: Expansion of the Cardiovascular Lymphatic Network via VEGF-C therapy in Atherosclerosis

Wajahat Dawood

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.

  1. Cardiovascular diseases (CVDs). World Health Organization. https://www.who.int/cardiovascular_diseases/en/. Published September 26, 2018. Accessed February 25, 2019.
  2. 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].
  3. 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
  4. 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
  5. 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
  6. 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