scholarly journals Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe

2020 ◽  
Vol 6 (50) ◽  
pp. eabc2697
Author(s):  
Kim Pin Yeo ◽  
Hwee Ying Lim ◽  
Chung Hwee Thiam ◽  
Syaza Hazwany Azhar ◽  
Caris Tan ◽  
...  
Keyword(s):  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Lymphatic Transport ◽  
Atherosclerotic Plaques ◽  
Tissue Fluid ◽  
Atherosclerosis Progression ◽  
Lymphatic Vasculature ◽  
Lesion Regression ◽  
Transport Of Macromolecules

A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance. Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood. We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe. Disruption of aortic lymph flow by lymphatic ligation promotes adventitial inflammation and development of atherosclerotic plaque in hypercholesterolemic mice and inhibits ezetimibe-induced atherosclerosis regression. Thus, progression of atherosclerotic plaques may result not only from increased entry of atherogenic factors into the arterial wall but also from reduced lymphatic clearance of these factors as a result of aortic lymph stasis. Our findings suggest that promoting lymphatic drainage might be effective for treating atherosclerosis.

Abstract 17: Reverse Cholesterol Transport Relies on a Functional Lymphatic Network

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Catherine Martel ◽  
Andrew M Platt ◽  
Marit Westerterp ◽  
Robert Bittman ◽  
Allan R Tall ◽  
...  
Keyword(s):  
Flow Cytometric Analysis ◽  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Cholesterol Transport ◽  
Atherosclerotic Plaques ◽  
Flow Cytometric ◽  
Macrophage Cholesterol Efflux ◽  
Lymphatic Vasculature ◽  
Lymphatic Network

Introduction: HDL accepts free cholesterol from cells within extravascular tissues and transports it to the liver for excretion. Little is known about how HDL-C leaves such tissues to reach the blood. HDL-C is found in lymph, but it is unclear if lymphatics are critical for mobilization of HDL-C from tissues. Methods & Results: We employed models of disrupted lymphatic drainage--one a surgical resection of lymphatics in the mouse tail and the other a genetic lack of skin lymphatics due to a mutation in VEGFR3--to quantify the role of lymphatic vessels in movement of HDL-C out of skin to plasma. We implanted bone marrow macrophages loaded with [ 3 H]-cholesterol in skin sites and then quantified [ 3 H]-cholesterol in plasma, liver, and feces. [ 3 H]-cholesterol movement into plasma was reduced by 80% in both models of disrupted lymphatics, and this result was unaffected by conditions of a leaky blood vessels. To ensure that this reduction reflected events between efflux and appearance of cholesterol in plasma rather than altered macrophage cholesterol efflux, we substituted [ 3 H]-cholesterol-loaded macrophages with congenic macrophages loaded with a fluorescently modified cholesterol compound that allowed us to monitor ABCA1/ABCG1-dependent efflux from individual macrophages in the same assays and models. Flow cytometric analysis of bodipy-cholesterol-loaded macrophages retrieved from injection sites revealed similar efflux in mice lacking functional lymphatics as in controls. Conclusions: Mobilization of HDL-C from extravascular tissues to plasma occurs through the lymphatic vasculature. Recent studies show that transport through lymphatic vessels is compromised by hypercholesterolemia. Hypercholesterolemia-induced impairments in lymphatic function may retard clearance of cholesterol from extravascular tissues, possibly including atherosclerotic plaques.

Abstract 56: Macrophage Reverse Cholesterol Transport in Mice Relies on The Lymphatic Vasculature

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Catherine Martel ◽  
Wenjun Li ◽  
Brian Fulp ◽  
Andrew Platt ◽  
Emmanuel L Gautier ◽  
...  
Keyword(s):  
Reverse Cholesterol Transport ◽  
Aortic Wall ◽  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Fecal Excretion ◽  
Lymphatic Transport ◽  
Cholesterol Transport ◽  
Transport Function ◽  
Peripheral Tissues ◽  
Lymphatic Vasculature

Reverse cholesterol transport (RCT) refers to mobilization of cholesterol on HDL particles (HDL-C) from extravascular tissues to plasma, ultimately for fecal excretion. Little is known about how HDL-C leaves peripheral tissues to reach plasma. We first used two models of disrupted lymphatic drainage from skin -one surgical and the other genetic- to quantitatively track RCT following injection of [3H]cholesterol-loaded macrophages upstream of blocked or absent lymphatic vessels. Macrophage RCT was markedly impaired in both models, even at sites with a leaky vasculature. Inhibited RCT was downstream of cholesterol efflux from macrophages, since macrophage efflux of a fluorescent cholesterol analogue (BODIPY-cholesterol) was not altered by impaired lymphatic drainage. We next addressed whether RCT was mediated by lymphatic vessels from the aortic wall by loading the aorta of donor atherosclerotic apoE-/- mice with [2H]6-labeled cholesterol and surgically transplanting these aortas into recipient apoE-/- mice that were treated with anti-VEGFR3 mAb to block lymphatic regrowth or with control mAb to allow such regrowth. [2H]-Cholesterol was retained in aortas of anti-VEGFR3 treated mice. Thus, the lymphatic vessel route is critical for RCT from multiple tissues, including the aortic wall. Therefore, supporting lymphatic transport function may facilitate cholesterol clearance in therapies aimed at reversing atherosclerosis.

Abstract 377: The Role of Impaired Lymphatic Drainage in Cardiac Transplantation

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Sydney C Ginn ◽  
Lanfang Wang ◽  
Rebecca D Levit
Keyword(s):  
Chronic Rejection ◽  
Cardiac Transplantation ◽  
Transplant Rejection ◽  
Lymphatic Drainage ◽  
Tissue Fluid ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
Cardiac Allografts ◽  
Pro Inflammatory Cytokines

Functional lymphatic drainage inherently modulates cardiac function by maintaining the immune response and tissue-fluid homeostasis. During cardiac transplantation, the lymphatic collecting vessels are severed at the time of heart excision and not surgically reconstructed in the recipient. The consequence resulting from impaired lymphatic drainage in transplanted hearts is unknown. We hypothesize disruption of lymphatic drainage potentiates chronic inflammation by impeding the egress of immune cells and pro-inflammatory cytokines out of the myocardium exacerbating transplant rejection. Methods: Banked human allograft biopsies were utilized to retrospectively evaluate lymphatic differences between patients that did and did not develop chronic transplant rejection from 1 week to 5 years after surgery. Immunofluorescence staining permitted quantification of normalized lymphatic vessel number and area throughout the lifespan of each cardiac allograft (n=24). Autopsy patients with non-cardiac related fatalities served as controls to delineate normal cardiac lymphatic distribution (n=6). Results: Patients without chronic rejection displayed an initial presence of lymphatic vasculature that steadily declined (n=12), while patients with chronic rejection exhibited a delayed increase in lymphatic development (n=12). Conclusions: These data show significant differences in lymphatic area between patients with and without chronic transplant rejection at critical timepoints, suggesting delayed lymphangiogenesis may correlate with rejection. Translational Impact: These preliminary human data support further investigation into lymphatic-modifying therapeutics to prolong the life of cardiac allografts.

scholarly journals Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis

2019 ◽  
Vol 81 (1) ◽  
pp. 535-560 ◽  
Author(s):  
Massimiliano Mazzone ◽  
Gabriele Bergers
Keyword(s):  
Immune Cells ◽  
Lymphatic Vessels ◽  
Tumor Vasculature ◽  
Therapeutic Approaches ◽  
Cancer Hallmarks ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Vessel Growth ◽  
Lymphatic Vasculature

Research over the last decades has provided strong evidence for the pivotal role of the tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T cell–mediated immunosurveillance. Conversely, tumor blood and lymphatic vessel growth is in part regulated by the immune system, with infiltrating innate as well as adaptive immune cells providing both immunosuppressive and various angiogenic signals. Thus, tumor angiogenesis and escape of immunosurveillance are two cancer hallmarks that are tightly linked and interregulated by cell constituents from compartments secreting both chemokines and cytokines. In this review, we discuss the implication and regulation of innate and adaptive immune cells in regulating blood and lymphatic angiogenesis in tumor progression and metastases. Moreover, we also highlight novel therapeutic approaches that target the tumor vasculature as well as the immune compartment to sustain and improve therapeutic efficacy in cancer.

Abstract 4: Lymphatic Vessels Mediate the Mobilization of Cardiac Progenitor Cells after Myocardial Infarction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Polina Goichberg ◽  
Maria Cimini ◽  
Antonio Cannata ◽  
Sergio Signore ◽  
Kanako Waight ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Progenitor Cells ◽  
Heart Diseases ◽  
Lymphatic Vessels ◽  
Mouse Heart ◽  
Cardiac Progenitor Cells ◽  
Myocardial Repair ◽  
Lymphatic Circulation ◽  
Lymphatic Vasculature

The delivery of adult cardiac progenitor cells (CPCs) or their activation in situ constitute an evolving approach for the treatment of heart failure. CPCs are endowed with regenerative capacity, producing differentiating myocytes and vascular structures in the course of homeostasis and upon injury. The regenerative function of CPCs is contingent to their ability to migrate to and engraft within the wounded area. Yet, the mechanisms governing CPC trafficking in the diseased myocardium are largely unknown. The lymphatic system is vital for tissue repair, and the role of the lymphatic vasculature in the trafficking of hematopoietic and cancer cells is well documented. We examined whether cardiac lymphatic vessels mediate the translocation of CPCs in the infarcted myocardium. By imaging of the heart from transgenic c-kit-GFP reporter mice, we found that as early as 4 hours after myocardial infarction (MI), uncommitted lineage-negative progenitors accumulated in the vicinity of the lymphatic vessels located in the region bordering the necrotic area. Histologically, extensive lymphangiogenesis was documented in the mouse heart in the acute (8-48 hours) and chronic (15-35 days) phases of infarct healing and scar formation. CPCs were detected traversing the wall of lymphatic vessels at different stages after MI, indicative of the functional role of the lymphatic circulation in the recruitment of primitive cells to the site of injury. Furthermore, isolated human CPCs exhibited chemotaxis and specific binding to the human lymphatic endothelial cells (LECs) in steady-state conditions and, increasingly, after exposure to an inflammatory cytokine, TNFα. CPCs performed trans-endothelial migration in vitro, and actively intravasated into the lumen of microvessels formed by LECs in three-dimensional matrices. Finally, our data suggest that sphingosine-1-phosphate (S1P)-stimulated signaling governs the interactions of CPCs with LECs. These findings on the direct role of lymphatic vasculature in CPC trafficking may contribute to the development of novel therapeutic modalities to increase mobilization of endogenous or transplanted CPCs, promoting myocardial repair in patients with ischemic heart diseases.

P4142PI3-kinase delta protects against atherosclerosis progression by governing regulatory T-cell biology

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Zierden ◽  
C Millarg ◽  
S Baldus ◽  
S Rosenkranz ◽  
E M Berghausen ◽  
...  
Keyword(s):  
T Cell ◽  
B Lymphocytes ◽  
Foam Cell ◽  
Cell Formation ◽  
Cd4 T Cell ◽  
Foam Cell Formation ◽  
Atherosclerotic Plaques ◽  
Cell Numbers ◽  
Atherosclerosis Progression

Abstract Introduction and purpose Atherosclerosis is a chronic inflammatory disease of arteries and represents the main underlying cause of death worldwide. Macrophages are major drivers of atherosclerosis by ingestion of lipoproteins, foam cell formation, and secretion of pro-inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B lymphocytes can shape the course of disease by promoting or mitigating inflammatory responses. Leukocytes highly express the phosphoinositide 3-kinase isoform delta (PI3Kd), exerting a key role in the regulation of immune responses including the activation, proliferation, differentiation, and effector function of lymphocytes. Since macrophages and lymphocytes are all major effectors of atherosclerosis, we aimed to understand the role of PI3Kd in these leukocytes during atherogenesis. Methods and results To investigate the role of haematopoietic PI3Kd in atherosclerosis, bone marrow from PI3Kd−/− or PI3Kd+/+ mice was transplanted into LDLR−/− mice. After 6 weeks of feeding on an atherogenic diet, PI3Kd−/− recipient LDLR−/− mice displayed significantly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T cells, and proatherogenic CD4+ T helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in LDLR−/− mice. Moreover, haematopoietic PI3Kd deficiency augmented macrophage accumulation in atherosclerotic plaques of LDLR−/− mice, whereas major macrophage functions including foam cell formation, efferocytosis, and cytokine secretion were unaffected by PI3Kd inactivation in these phagocytes. However, haematopoietic PI3Kd deficiency led to depletion of atheroprotective B-1 cells and reduction of proatherogenic B-2 cells in LDLR−/− mice. Moreover, haematopoietic PI3Kd deficiency caused a significant reduction of regulatory CD4+ T cells (Tregs) in plaques, para-aortic lymph nodes, and spleen of LDLR−/− mice. Furthermore, PI3Kd−/− Tregs exhibited reduced secretion of anti-inflammatory cytokines IL-10 and TGF-b as well as impaired suppression of CD4+ T-cell proliferation. Consequently, adoptive transfer of PI3Kd+/+ Tregs fully constrains the atherosclerotic burden in PI3Kd−/− transplanted LDLR−/− mice without affecting B cell numbers. Conclusions We demonstrate that PI3Kd plays a crucial role in B lymphocytes, Th1 cells, and Tregs during atherogenesis. Lack of PI3Kd signalling in atheroprotective Treg responses outplays its impact on proatherogenic Th1 responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis progression. Acknowledgement/Funding Center for Molecular Medicine Cologne (CMMC) and the Marga and Walter Boll-Stiftung

scholarly journals Lymphatics and Lymphangiogenesis in the Eye

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Shintaro Nakao ◽  
Ali Hafezi-Moghadam ◽  
Tatsuro Ishibashi
Keyword(s):  
Tumor Metastasis ◽  
Vision Loss ◽  
Transplant Rejection ◽  
Lymphatic Vessels ◽  
The Body ◽  
Corneal Transplant ◽  
Tissue Fluid ◽  
Ocular Diseases ◽  
Pathological Conditions

Lymphatic is a prerequisite for the maintenance of tissue fluid balance and immunity in the body. A body of evidence also shows that lymphangiogenesis plays important roles in the pathogenesis of diseases such as tumor metastasis and inflammation. The eye was thought to lack lymphatic vessels except for the conjunctiva; however, advances in the field, including the identification of lymphatic endothelial markers (e.g., LYVE-1 or podoplanin) and lymphangiogenic factors (e.g., VEGF-C), have revealed the exsitence and possible roles of lymphatics and lymphangiogenesis in the eye. Recent studies have shown that corneal limbus, ciliary body, lacrimal gland, orbital meninges, and extraocular muscles contain lymphatic vessels and that the choroid might have a lymphatic-like system. There is no known lymphatic outflow from the eye. However, several lymphatic channels including uveolymphatic pathway might serve the ocular fluid homeostasis. Furthermore, lymphangiogenesis plays important roles in pathological conditions in the eye including corneal transplant rejection and ocular tumor progression. Yet, the role of lymphangiogenesis in most eye diseases, especially inflammatory disease or edema, remains unknown. A better understanding of lymphatic and lymphangiogenesis in the eye will open new therapeutic opportunities to prevent vision loss in ocular diseases.

scholarly journals Hypercholesterolemia and Lymphatic Defects: The Chicken or the Egg?

2021 ◽  
Vol 8 ◽  
Author(s):  
Takuro Miyazaki ◽  
Akira Miyazaki
Keyword(s):  
Causal Relationship ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Lymphatic Invasion ◽  
Dietary Lipids ◽  
Cell Trafficking ◽  
Tissue Fluid ◽  
Lipoprotein Composition ◽  
Factor C

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.

scholarly journals Lymphatic endothelial-cell expressed ACKR3 is dispensable for postnatal lymphangiogenesis and lymphatic drainage function in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249068
Author(s):  
Elena C. Sigmund ◽  
Lilian Baur ◽  
Philipp Schineis ◽  
Jorge Arasa ◽  
Victor Collado-Diaz ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Knockout Mouse ◽  
Lymphatic Endothelial Cell ◽  
Peptide Hormone ◽  
Lymphatic Drainage ◽  
Adult Mice ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
And Function

Atypical chemokine receptor ACKR3 (formerly CXCR7) is a scavenging receptor that has recently been implicated in murine lymphatic development. Specifically, ACKR3-deficiency was shown to result in lymphatic hyperplasia and lymphedema, in addition to cardiac hyperplasia and cardiac valve defects leading to embryonic lethality. The lymphatic phenotype was attributed to a lymphatic endothelial cell (LEC)-intrinsic scavenging function of ACKR3 for the vascular peptide hormone adrenomedullin (AM), which is also important during postnatal lymphangiogenesis. In this study, we investigated the expression of ACKR3 in the lymphatic vasculature of adult mice and its function in postnatal lymphatic development and function. We show that ACKR3 is widely expressed in mature lymphatics and that it exerts chemokine-scavenging activity in cultured murine skin-derived LECs. To investigate the role of LEC-expressed ACKR3 in postnatal lymphangiogenesis and function during adulthood, we generated and validated a lymphatic-specific, inducible ACKR3 knockout mouse. Surprisingly, in contrast to the reported involvement of ACKR3 in lymphatic development, our analyses revealed no contribution of LEC-expressed ACKR3 to postnatal lymphangiogenesis, lymphatic morphology and drainage function.

Abstract 569: Lymphatic Function Is Impaired Before Atherosclerosis Onset in a Model of Atherosclerosis-prone Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Andreea Milasan ◽  
Marie-Elaine Clavet-Lanthier ◽  
Gaetan Mayer ◽  
Catherine Martel
Keyword(s):  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Lymphatic Transport ◽  
Cellular Transport ◽  
Aortic Sinus ◽  
Lymphatic Function ◽  
Preliminary Results ◽  
Atherosclerosis Progression

Introduction: Macrophages and cholesterol are the two main constituents driving the inflammatory response that characterizes atherosclerosis. In a recent study, the lymphatic system has been identified as a novel prerequisite player in the removal of cholesterol out of the atherosclerotic lesion. It has been shown that without a functional lymphatic network, cholesterol gets trapped in the artery wall. The lymphatic vessels are composed of two main components, namely the absorptive capillaries, responsible for the uptake of the cells, molecules and fluid, and the collecting vessels, characterized by pumping units (lymphangions) that are propelling the lymphatic content toward the blood circulation in a unidirectional manner. The relative roles of the lymphatic capillaries and collectors in the context of atherosclerotic disease are still unclear. Methods and results: Lymphatic function has been evaluated in 3-month old atherosclerosis-prone (LDLR-/-; hApoB100+/+, also called ATX mice), LDLR-/-, atherosclerosis-protected (PCSK9-/- mice, deficient in a convertase that induces the degradation of the LDL receptor) and wild-type (WT) mice. Our preliminary data show that, like LDLR-/- mice, pre-atherosclerotic ATX mice exhibit impaired lymphatic cellular transport. Immunohistochemistry and immunofluorescence imaging portrays a relatively normal number of sprouting and diameter of lymphatic vessel capillaries in the adventitial layer of the aortic sinus and in the skin dermis of ATX mice compared to WT or PCSK9-/- animals. Conclusions: Our preliminary results suggest that lymphatic transport is impaired even before the onset of atherosclerosis, and that i) the LDLR is associated with lymphatic vessel function, and that ii) the collecting lymphatic vessels are most likely responsible for the impairment in lymphatic dysfunction in LDLR-/- and ATX mice. These preliminary results suggest that characterizing the functional pumping capacity of the collecting vessels would be a prerequisite in understanding the interplay between atherosclerosis progression and lymphatic transport. We hope that in the long run we will be able to identify new therapeutic targets to enhance lymphatic transport and ultimately limit atherosclerosis progression.

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