The Effect of Lymphangiogenesis in Transplant Arteriosclerosis

Abstract

BACKGROUND: Transplant arteriosclerosis is a major complication in long-term survivors of heart transplantation. Increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis, but how lymphangiogenesis affects this process is unknown. METHODS: Vascular allografts were transplanted among various combinations of mice, including wild-type, Lyve1 -CreER T2 ;R26-tdTomato, CAG-Cre-tdTomato, severe combined immune deficiency, Ccr2 KO , Foxn1 KO , and lghm / lghd KO mice. Whole-mount staining and 3-dimensional reconstruction identified lymphatic vessels within the grafted arteries. Lineage tracing strategies delineated the cellular origin of lymphatic endothelial cells. Adeno-associated viral vectors and a selective inhibitor were used to regulate lymphangiogenesis. RESULTS: Lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 (chemokine [C-C motif] ligand 21) were associated with these immune structures. Fibroblasts in the vascular allografts released VEGF-C (vascular endothelial growth factor C), which stimulated lymphangiogenesis into the grafts. Inhibition of VEGF-C signaling inhibited lymphangiogenesis, neointima formation, and adventitial fibrosis of vascular allografts. These studies identified VEGF-C released from fibroblasts as a signal stimulating lymphangiogenesis extending from the host into the vascular allografts. CONCLUSIONS: Formation of lymphatic vessels plays a key role in the immune response to vascular transplantation. The inhibition of lymphangiogenesis may be a novel approach to prevent transplant arteriosclerosis.

Characterization of Atherosclerotic Mice Reveals a Sex-Dependent Susceptibility to Plaque Calcification but No Major Changes in the Lymphatics in the Arterial Wall

“…Lymphatics have been shown to be present in the adventitia of great vessels, but their function is not clear yet. Arterial lymphatics are widely believed to be beneficial in atherosclerosis by clearing cholesterol and immune cells from atherosclerotic plaques, but a new study recently showed that arterial lymphatics are one of the factors contributing to the development of transplant arteriosclerosis and that the inhibition of lymphangiogenesis would possibly prevent transplant arteriosclerosis by inhibiting the immune response [34][35][36][37][43][44][45]. Despite the fact that arterial lymphatics have been investigated in various diseases [38][39][40], a detailed characterization of the lymphatic vasculature within the arterial wall has not been carried out to date.…”

Role of the Lymphatics in Cardiac Disease

“…80,81 Vascular remodeling in allografts is known to result from immunologic rejection, which implicates the lymphatic system owing to its crucial role in the alloimmune response (immune response to nonself antigens). 82 During transplantation, donor lymphatic vessels are not anastomosed to that of the recipient. 83 Instead, the inflamed environment activates donor passenger leukocytes, which migrate out of the graft via the severed ends of donor lymphatic vessels and are taken up by the lymphatic capillaries of the recipient to be trafficked to the lymph nodes.…”

Neutrophil extracellular traps promoting fibroblast activation and aggravating limb ischemia through Wnt5a pathway

“…Both control and ischemia tissues were fully digested. The cell pellet was suspended in PBS and were subjected to single cell RNA sequencing as described previously [15,16]. A total of 63,645 cells remained post-filtering and data were normalized by "LogNormalize".…”