Hypercholesterolemia and Lymphatic Defects: The Chicken or the Egg?

Abstract

Lymphatic vessels are necessary for maintaining tissue fluid balance, trafficking of immune cells, and transport of dietary lipids. Growing evidence suggest that lymphatic functions are limited under hypercholesterolemic conditions, which is closely related to atherosclerotic development involving the coronary and other large arteries. Indeed, ablation of lymphatic systems by Chy-mutation as well as depletion of lymphangiogenic factors, including vascular endothelial growth factor-C and -D, in mice perturbs lipoprotein composition to augment hypercholesterolemia. Several investigations have reported that periarterial microlymphatics were attracted by atheroma-derived lymphangiogenic factors, which facilitated lymphatic invasion into the intima of atherosclerotic lesions, thereby modifying immune cell trafficking. In contrast to the lipomodulatory and immunomodulatory roles of the lymphatic systems, the critical drivers of lymphangiogenesis and the details of lymphatic insults under hypercholesterolemic conditions have not been fully elucidated. Interestingly, cholesterol-lowering trials enable hypercholesterolemic prevention of lymphatic drainage in mice; however, a causal relationship between hypercholesterolemia and lymphatic defects remains elusive. In this review, the contribution of aberrant lymphangiogenesis and lymphatic cholesterol transport to hypercholesterolemic atherosclerosis was highlighted. The causal relationship between hypercholesterolemia and lymphatic insults as well as the current achievements in the field were discussed.

Identification of diagnostic biomarkers and therapeutic targets in peripheral immune landscape from coronary artery disease

“…On the one hand, it may promote the expression of CD36, activates JAK1/STAT3, strengthens the lipid loading of macrophages, and accelerates the formation of foam cells; On the other hand, it can also reduce the inflammatory response by promoting the TGF-β and inhibiting IL-6, promotes the formation of plaque fibrous cap by increasing α-SMA, and enhances cholesterol efflux by up-regulating SR-B1. In addition, IL13RA1 also promotes the production of VEGF-C, which is believed to accelerate the process of plaque inflammation and lipid accumulation by promoting the formation of pathological lymphatics in the early stage of atherosclerosis [ 48 ], and also plays an active role in plaque regression and cardiac function recovery in the later stage [ 49 ].…”

Calpain and Cardiometabolic Diseases

“…Lymphatic vessels exert a pivotal role in the regulation of fluid homeostasis, the conveyance of immune cells, and the transportation of lipids absorbed from dietary sources [60]. Recent studies have revealed that dysfunctional lymphatic vessels contribute significantly to the pathogenesis and progression of atherosclerosis within major arterial conduits.…”

“…The lymphocyte migration, originating from peripheral organs towards their respective lymph nodes, exhibited a discernible reduction concomitant with the onset of dyslipidemia [60]. Such lymphatic abnormality was subsequently ameliorated through the deficiency of conventional calpains, specifically within the lymphatic endothelial cells or myeloid cells [65].…”

Interaction Between Blood Vasculatures and Lymphatic Vasculatures During Inflammation

“…Although the VEGF family is also involved in lymphangiogenesis, which may be related to VEGF-C and VEGF-D. 9 In chronic inflammatory conditions, such as in a mouse model of chronic colitis, VEGF-C enhances local lymphatic drainage and leads to the normalization of gut microbiota. 10 The high expression of VEGF-C and VEGF-D at the sites of inflammatory injury may be induced by macrophages 11 and mast cells 12 among others. VEGFR-3 is widely expressed in lymphatic endothelial cells (LECs) and can be activated by VEGF-C and VEGF-D, inducing LEC proliferation and migration.…”