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 Vegfr3-tdTomato, a reporter mouse for microscopic visualization of lymphatic vessel by multiple modalities

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0249256
Author(s):  
Esther Redder ◽  
Nils Kirschnick ◽  
Stefanie Bobe ◽  
René Hägerling ◽  
Nils Rouven Hansmeier ◽  
...  
Keyword(s):  
Laser Scanning ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Regulatory Elements ◽  
Dietary Lipids ◽  
Epifluorescence Microscopy ◽  
Lymph Vessel ◽  
Confocal Laser ◽  
Cell Trafficking ◽  
Tissue Fluid

Lymphatic vessels are indispensable for tissue fluid homeostasis, transport of solutes and dietary lipids and immune cell trafficking. In contrast to blood vessels, which are easily visible by their erythrocyte cargo, lymphatic vessels are not readily detected in the tissue context. Their invisibility interferes with the analysis of the three-dimensional lymph vessel structure in large tissue volumes and hampers dynamic intravital studies on lymphatic function and pathofunction. An approach to overcome these limitations are mouse models, which express transgenic fluorescent proteins under the control of tissue-specific promotor elements. We introduce here the BAC-transgenic mouse reporter strain Vegfr3-tdTomato that expresses a membrane-tagged version of tdTomato under control of Flt4 regulatory elements. Vegfr3-tdTomato mice inherited the reporter in a mendelian fashion and showed selective and stable fluorescence in the lymphatic vessels of multiple organs tested, including lung, kidney, heart, diaphragm, intestine, mesentery, liver and dermis. In this model, tdTomato expression was sufficient for direct visualisation of lymphatic vessels by epifluorescence microscopy. Furthermore, lymph vessels were readily visualized using a number of microscopic modalities including confocal laser scanning, light sheet fluorescence and two-photon microscopy. Due to the early onset of VEGFR-3 expression in venous embryonic vessels and the short maturation time of tdTomato, this reporter offers an interesting alternative to Prox1-promoter driven lymphatic reporter mice for instance to study the developmental differentiation of venous to lymphatic endothelial cells.

scholarly journals Vegfr3-tdTomato, a reporter mouse for microscopic visualization of lymphatic vessel by multiple modalities

2021 ◽  
Author(s):  
Esther Redder ◽  
Nils Kirschnick ◽  
René Hägerling ◽  
Nils Hansmeier ◽  
Friedemann Kiefer
Keyword(s):  
Laser Scanning ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Regulatory Elements ◽  
Dietary Lipids ◽  
Epifluorescence Microscopy ◽  
Lymph Vessel ◽  
Confocal Laser ◽  
Cell Trafficking ◽  
Tissue Fluid

AbstractLymphatic vessels are indispensable for tissue fluid homeostasis, transport of solutes and dietary lipids and immune cell trafficking. In contrast to blood vessels, which are easily visible by their erythrocyte cargo, lymphatic vessels are not readily detected in the tissue context. Their invisibility interferes with the analysis of the three-dimensional lymph vessel structure in large tissue volumes and hampers dynamic intravital studies on lymphatic function and pathofunction. An approach to overcome these limitations are mouse models, which express transgenic fluorescent proteins under the control of tissue-specific promotor elements.We introduce here the BAC-transgenic mouse reporter strain Vegfr3-tdTomato that expresses a membrane-tagged version of tdTomato under control of Flt4 regulatory elements. Vegfr3-tdTomato mice inherited the reporter in a mendelian fashion and showed selective and stable fluorescence in the lymphatic vessels of multiple organs tested, including lung, kidney, heart, diaphragm, intestine, mesentery and dermis. In this model, tdTomato expression was sufficient for direct visualisation of lymphatic vessels by epifluorescence microscopy. Furthermore, lymph vessels were readily visualized using a number of microscopic modalities including confocal laser scanning, light sheet fluorescence and two-photon microscopy. Due to the early onset of VEGFR-3 expression in venous embryonic vessels and the short maturation time of tdTomato, this reporter offers an interesting alternative to Prox1-promoter driven lymphatic reporter mice for instance to study the developmental differentiation of venous to lymphatic endothelial cells.

scholarly journals When form meets function: the cells and signals that shape the lymphatic vasculature during development

Development ◽  
2021 ◽  
Vol 148 (11) ◽  
Author(s):  
Mathias Francois ◽  
Anna Oszmiana ◽  
Natasha L. Harvey
Keyword(s):  
Network Formation ◽  
Immune Cell ◽  
Lymphatic Endothelial Cell ◽  
Dietary Lipids ◽  
Cell Trafficking ◽  
Tissue Fluid ◽  
Cellular Events ◽  
Formation Function ◽  
Lymphatic Vasculature ◽  
Lymphatic Network

ABSTRACT The lymphatic vasculature is an integral component of the cardiovascular system. It is essential to maintain tissue fluid homeostasis, direct immune cell trafficking and absorb dietary lipids from the digestive tract. Major advances in our understanding of the genetic and cellular events important for constructing the lymphatic vasculature during development have recently been made. These include the identification of novel sources of lymphatic endothelial progenitor cells, the recognition of lymphatic endothelial cell specialisation and heterogeneity, and discovery of novel genes and signalling pathways underpinning developmental lymphangiogenesis. Here, we review these advances and discuss how they inform our understanding of lymphatic network formation, function and dysfunction.

scholarly journals Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges

2019 ◽  
Vol 8 (4) ◽  
pp. 495 ◽  
Author(s):  
Csányi ◽  
Singla
Keyword(s):  
Reverse Cholesterol Transport ◽  
Immune Cell ◽  
Imaging Techniques ◽  
Dietary Lipids ◽  
Cholesterol Transport ◽  
Cell Trafficking ◽  
Tissue Fluid ◽  
Lymphatic Function ◽  
Cardiovascular Tissue ◽  
Lymphatic Circulation

The lymphatic network is well known for its role in the maintenance of tissue fluid homeostasis, absorption of dietary lipids, trafficking of immune cells, and adaptive immunity. Aberrant lymphatic function has been linked to lymphedema and immune disorders for a long time. Discovery of lymphatic cell markers, novel insights into developmental and postnatal lymphangiogenesis, development of genetic mouse models, and the introduction of new imaging techniques have improved our understanding of lymphatic function in both health and disease, especially in the last decade. Previous studies linked the lymphatic vasculature to atherosclerosis through regulation of immune responses, reverse cholesterol transport, and inflammation. Despite extensive research, many aspects of the lymphatic circulation in atherosclerosis are still unknown and future studies are required to confirm that arterial lymphangiogenesis truly represents a therapeutic target in patients with cardiovascular disease. In this review article, we provide an overview of factors and mechanisms that regulate lymphangiogenesis, summarize recent findings on the role of lymphatics in macrophage reverse cholesterol transport, immune cell trafficking and pathogenesis of atherosclerosis, and present an overview of pharmacological and genetic strategies to modulate lymphatic vessel density in cardiovascular tissue.

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.

Characterization of Near-Infrared Functional Lymphatic Imaging in the Rat Tail Model

2013 ◽  
Author(s):  
Michael Weiler ◽  
J. Brandon Dixon
Keyword(s):  
Near Infrared ◽  
Immune Cell ◽  
Imaging Modality ◽  
Lymphatic Vessels ◽  
The Body ◽  
Cell Trafficking ◽  
Nir Imaging ◽  
Lymphatic Vasculature ◽  
Rat Tail Model ◽  
Lymphatic Imaging

The lymphatic vasculature is present in nearly every tissue of the body to serve essential functions in fluid homeostasis, immune cell trafficking, and lipid transport, and it has been implicated in the progression of several diseases. Despite the critical roles that this system performs, very little is known about the lymphatic vasculature in comparison to the blood vasculature, which can be attributed, in part, to the difficulty associated with imaging lymphatic vessels. With the growing interest in studying lymphatics, near-infrared (NIR) imaging has emerged in the literature as a novel lymphatic imaging modality to simultaneously improve spatial resolution to visualize small initial lymphatics and increase temporal resolution to capture the dynamic lymphatic pump function responsible for fluid propulsion.

scholarly journals Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1344
Author(s):  
Kim Pin Yeo ◽  
Hwee Ying Lim ◽  
Veronique Angeli
Keyword(s):  
Immune Cell ◽  
Lymphatic Vessels ◽  
Cardiovascular Complications ◽  
Chronic Inflammatory Disease ◽  
Cell Trafficking ◽  
Functional Roles ◽  
New Findings ◽  
Lymphatic Vasculature ◽  
Acute And Chronic Inflammation ◽  
Progression Of Atherosclerosis

In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will discuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide. The progression of atherosclerosis is associated with morphological and functional alterations in lymphatic vessels draining the diseased artery. These defects in the lymphatic vasculature impact the inflammatory response in atherosclerosis by affecting immune cell trafficking, lymphoid neogenesis, and clearance of macromolecules in the arterial wall. Based on these new findings, we propose that targeting lymphatic function could be considered in conjunction with existing drugs as a treatment option for atherosclerosis.

scholarly journals Dynamic interactions of lymphatic vessels at the hair follicle stem cell niche during hair regeneration

2019 ◽  
Author(s):  
Daniel Peña-Jimenez ◽  
Silvia Fontenete ◽  
Diego Megias ◽  
Coral Fustero-Torre ◽  
Osvaldo Graña-Castro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hair Follicle ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Mouse Skin ◽  
Tissue Level ◽  
Mouse Genetics ◽  
Cell Trafficking ◽  
Dependent Manner ◽  
Hair Follicle Stem Cell

AbstractLymphatic vessels (LV) are essential for skin fluid homeostasis and immune cell trafficking, but whether LV are associated with hair follicle (HF) regeneration is not known. Here, by using steady and live imaging approaches in mouse skin, we show that lymphatic capillaries distribute to the anterior permanent region of individual HF and interconnect neighboring HF at the level of the HF bulge, in a hair follicle stem cell (HFSC)-dependent manner. LV further connect individual HF in triads and dynamically flow across the skin. Interestingly, at the onset of the physiological HFSC activation, or upon pharmacological or genetic induction of HF growth, LV transiently expand their caliber suggesting an increased tissue drainage capacity. Interestingly, the physiological LV caliber increase is associated with a distinct gene expression correlated to ECM and cytoskeletal reorganization. Using mouse genetics, we show that the depletion of LV blocks the pharmacological induction of HF growth. Our findings define LV as components of the HFSC niche, coordinating HF connections at tissue-level, and provide insight into their functional contribution to HF regeneration.

256. Ovarian lymphatic vascular development is hormonally regulated and Adamts1-dependent

2008 ◽  
Vol 20 (9) ◽  
pp. 56
Author(s):  
H. M. Brown ◽  
R. L. Robker ◽  
D. L. Russell
Keyword(s):  
Granulosa Cells ◽  
Hormonal Regulation ◽  
Lymphatic System ◽  
Immune Cell ◽  
Vascular Development ◽  
Lymphatic Vessels ◽  
Hormonal Control ◽  
Cell Trafficking ◽  
Reproductive Tissues ◽  
Reproductive Cycles

The lymphatic system is important for return of extra-vascular fluid to the blood circulation, conductance of hormones and immune cell trafficking. Delicate hormonal control of fluid conductance during reproductive cycles is exemplified by the ovarian hyperstimulation syndrome, a dangerous condition of hypovolemia caused by fluid accumulation in the abdomen and reproductive tissues, in response to hormonal hyperstimulation. This study is the first to investigate the relationship between ovarian lymphatic development and follicle growth. Quantitative morphometric analysis of vessel size and number in mouse ovary revealed, for the first time, that the ovarian lymphatic vasculature develops postnatally and in synchrony with the induction of ovarian CYP19a1 (Aromatase); the time when secondary follicles become FSH-responsive and estrogenic. Mechanistically, we found that the FSH-analogue eCG mediates induction of lymphatic vascular endothelial growth factor Vegfd and the receptor Vegfr3 (Flt4) in granulosa cells. Importantly, stimulation with eCG also enhanced ovarian lymphatic vessel number and size. However, formation of ovarian lymphatics also required the matrix-remodelling protease Adamts1, since ovaries from Adamts1−/− mice failed to undergo normal lymphatic vascular development. Treatment of Adamts1 null mice with eCG significantly increased the number and size of ovarian lymphatic vessels, however, the vessels were still smaller and fewer in number than wildtypes. These combined results indicate that the ovarian lymphatic system develops in response to hormonal signals, which promote folliculogenesis, through induction of lymphangiogenic factors in granulosa cells; as well as involving Adamts1-dependent mechanisms. This study is the first demonstration of the novel principle of hormonal regulation of lymphangiogenesis in any tissue and suggests a requirement for functional lymphatics during normal folliculogenesis. In addition our results inform the elucidation of the tightly regulated processes that control fluid dynamics and immune cell surveillance within reproductive tissues.

Engineering Tools for Studying the Interplay Between Mechanics and Biology in Lymphatic Lipid Transport

2010 ◽  
Author(s):  
J. Brandon Dixon
Keyword(s):  
Immune Cell ◽  
Mechanical Load ◽  
Contractile Function ◽  
Lymphatic Vessels ◽  
Dietary Lipid ◽  
The Body ◽  
Lipid Transport ◽  
Cell Trafficking

The lymphatic vasculature extends through most tissues of the body and plays an essential role in maintaining fluid balance, immune cell trafficking, and lipid transport. Nearly all dietary lipid is transported from the intestine to the circulation via the lymphatic system in the form of triglyceride-rich lipoproteins called chylomicrons. This process can be described through two different mechanisms: 1) entry of the chylomicron into the initial lymphatic vessels of the small intestine, known as lacteals, and 2) the transport of these chylomicrons through the larger collecting lymphatics by a complex and coordinated system of individual contracting vessel units (lymphangions) and valve leaflets. We describe here a set of in vitro and in vivo tools we have developed to study the mechanisms that modulate lipid transport under these two different paradigms and show how these tools are uncovering important biological features involved in these mechanisms. Lymphatic pump function is known to be sensitive to the mechanical load on the vessel as the contractility of isolated vessels has been shown to be both shear and stretch sensitive [1], yet whether these mechanisms are important in regulating contractile function in vivo remains uncertain.

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