scholarly journals Molecular Mechanisms Controlling Lymphatic Endothelial Junction Integrity

2021 ◽  
Vol 8 ◽  
Author(s):  
Pieter R. Norden ◽  
Tsutomu Kume
Keyword(s):  
Molecular Mechanisms ◽  
Vascular System ◽  
Current Knowledge ◽  
Lymphatic Vessels ◽  
Circulatory System ◽  
Lymphatic Endothelial Cell ◽  
Basement Membranes ◽  
Cell Junctions ◽  
Lipid Absorption ◽  
Tissue Fluid

The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the nature of lymphatic vessel abnormalities and disease in humans is complex and poorly understood. The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. In this review, we discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We also provide current knowledge related to key pathways and factors such as VEGF and RhoA/ROCK signaling that control lymphatic endothelial cell junctional integrity.

scholarly journals Lymphatic Endothelial Cell Plasticity in Development and Disease

Physiology ◽  
2017 ◽  
Vol 32 (6) ◽  
pp. 444-452 ◽  
Author(s):  
Wanshu Ma ◽  
Guillermo Oliver
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Lymphatic Endothelial Cell ◽  
Lipid Absorption ◽  
Tissue Fluid ◽  
Mammalian Embryo ◽  
Fate Specification ◽  
Lymphatic Vasculature ◽  
Functional Features

The lymphatic vasculature is crucial for maintaining tissue-fluid homeostasis, providing immune surveillance and mediating lipid absorption. The lymphatic vasculature is tightly associated with the blood vasculature, although it exhibits distinct morphological and functional features. Endothelial cells (ECs) lineage fate specification is determined during embryonic development; however, accumulating evidence suggests that differentiated ECs exhibit remarkable heterogeneity and plasticity. In this review, we provide an overview of the molecular mechanisms promoting lymphatic cell fate specification in the mammalian embryo. We also summarize available data suggesting that lymphatic EC fate is reprogrammable in normal and pathological settings. We further discuss the possible advantages of cell fate manipulation to treat certain disorders associated with lymphatic dysfunction.

scholarly journals Vascular endothelial cell specification in health and disease

Angiogenesis ◽  
2021 ◽  
Author(s):  
Corina Marziano ◽  
Gael Genet ◽  
Karen K. Hirschi
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Current Knowledge ◽  
Vascular Malformations ◽  
Immune Surveillance ◽  
Vascular Endothelial Cell ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
The Body ◽  
Vascular Networks

AbstractThere are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

scholarly journals The Transcriptional Control of Lymphatic Vascular Development

Physiology ◽  
2011 ◽  
Vol 26 (3) ◽  
pp. 146-155 ◽  
Author(s):  
Mathias Francois ◽  
Natasha L. Harvey ◽  
Benjamin M. Hogan
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Developmental Process ◽  
Vascular Development ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
Transcriptional Networks ◽  
Genetic Manipulations

More than 100 years ago, Florence Sabin suggested that lymphatic vessels develop by sprouting from preexisting blood vessels, but it is only over the past decade that the molecular mechanisms underpinning lymphatic vascular development have begun to be elucidated. Genetic manipulations in mice have identified a transcriptional hub comprised of Prox1, CoupTFII, and Sox18 that is essential for lymphatic endothelial cell fate specification. Recent work has identified a number of additional transcription factors that regulate later stages of lymphatic vessel differentiation and maturation. This review highlights recent advances in our understanding of the transcriptional control of lymphatic vascular development and reflects on efforts to better understand the activities of transcriptional networks during this discrete developmental process. Finally, we highlight the transcription factors associated with human lymphatic vascular disorders, demonstrating the importance of understanding how the activity of these key molecules is regulated, with a view toward the development of innovative therapeutic avenues.

scholarly journals Targeting Platelet in Atherosclerosis Plaque Formation: Current Knowledge and Future Perspectives

2020 ◽  
Vol 21 (24) ◽  
pp. 9760
Author(s):  
Lei Wang ◽  
Chaojun Tang
Keyword(s):  
Risk Factors ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Current Knowledge ◽  
Vascular Inflammation ◽  
Plaque Formation ◽  
Inflammatory Factors ◽  
Future Perspectives ◽  
Atherosclerotic Plaque Formation

Besides their role in hemostasis and thrombosis, it has become increasingly clear that platelets are also involved in many other pathological processes of the vascular system, such as atherosclerotic plaque formation. Atherosclerosis is a chronic vascular inflammatory disease, which preferentially develops at sites under disturbed blood flow with low speeds and chaotic directions. Hyperglycemia, hyperlipidemia, and hypertension are all risk factors for atherosclerosis. When the vascular microenvironment changes, platelets can respond quickly to interact with endothelial cells and leukocytes, participating in atherosclerosis. This review discusses the important roles of platelets in the plaque formation under pro-atherogenic factors. Specifically, we discussed the platelet behaviors under disturbed flow, hyperglycemia, and hyperlipidemia conditions. We also summarized the molecular mechanisms involved in vascular inflammation during atherogenesis based on platelet receptors and secretion of inflammatory factors. Finally, we highlighted the studies of platelet migration in atherogenesis. In general, we elaborated an atherogenic role of platelets and the aspects that should be further studied in the future.

scholarly journals Induction of lymphatic endothelial cell differentiation in embryoid bodies

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1214-1216 ◽  
Author(s):  
Ruediger Liersch ◽  
Filip Nay ◽  
Lingge Lu ◽  
Michael Detmar
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Es Cells ◽  
Embryonic Stem ◽  
Lymphatic Endothelial Cell ◽  
Embryoid Bodies ◽  
Lymphatic Endothelial Cells ◽  
Vessel Formation

AbstractThe molecular mechanisms that regulate the formation of the lymphatic vascular system remain poorly characterized. Whereas studies in embryonic stem (ES) cells have provided major new insights into the mechanisms of blood vessel formation, the development of lymphatic endothelium has not been previously observed. We established embryoid bodies (EBs) from murine ES cells in the presence or absence of lymphangiogenic growth factors. We found that lymphatic endothelial cells develop at day 18 after EB formation. These cells express CD31 and the lymphatic lineage markers Prox-1 and Lyve-1, but not the vascular marker MECA-32, and they frequently sprout from preexisting blood vessels. Lymphatic vessel formation was potently promoted by VEGF-A and VEGF-C but not by bFGF. Our results reveal, for the first time, that ES cells can differentiate into lymphatic endothelial cells, and they identify the EB assay as a powerful new tool to dissect the molecular mechanisms that control lymphatic vessel formation.

scholarly journals Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning

2009 ◽  
Vol 207 (1) ◽  
pp. 17-27 ◽  
Author(s):  
Trung H.M. Pham ◽  
Peter Baluk ◽  
Ying Xu ◽  
Irina Grigorova ◽  
Alex J. Bankovich ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
Sphingosine Kinase ◽  
Peyer's Patches ◽  
Cell Junctions ◽  
Peyer’S Patches ◽  
Cellular Source ◽  
Lymphocyte Egress

Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lymphatic endothelium. We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre+ Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Gαi-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell–cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation.

The lymphatic system

2017 ◽  
Author(s):  
Sinem Karaman ◽  
Aleksanteri Aspelund ◽  
Michael Detmar ◽  
Kari Alitalo
Keyword(s):  
Lymph Nodes ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Circulatory System ◽  
Dietary Fats ◽  
Venous Circulation ◽  
Tumour Metastasis ◽  
System P ◽  
Vegf Family Members ◽  
Endothelial Growth Factor

The lymphatic vascular system is an integral component of the circulatory system; it forms a one-way conduit that transports tissue interstitial components back to the venous circulation through lymph nodes. Lymphatic vessels extend to most tissues and contribute to the regulation of interstitial fluid homeostasis, trafficking of immune cells, and absorption of dietary fats from the gut. Developmentally, lymphatic vessels originate from embryonic veins and specialized angioblasts. A number of molecules have been identified in the commitment of endothelial cells to the lymphatic lineage, and the sprouting, expansion and maturation of the lymphatic vascular tree. Importantly, the vascular endothelial growth factor (VEGF) family members VEGFC and VEGFD, together with their receptors VEGFR2 and VEGFR3 have been implicated as critical regulators of lymphangiogenesis. Lymphatic vessels are involved in several human diseases, including cancer, where they contribute to tumour metastasis, the leading cause of cancer-related deaths. Lymphatic vessels regulate immune responses against foreign pathogens by transporting leucocytes to lymph nodes, but are also in involved in the regulation of self-tolerance. Defects in the lymphatic vascular system are causal for the development of lymphoedema.

scholarly journals Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1200
Author(s):  
Nolwenn Tessier ◽  
Fatma Moawad ◽  
Nada Amri ◽  
Davide Brambilla ◽  
Catherine Martel
Keyword(s):  
Cardiovascular Disease ◽  
Drug Delivery ◽  
New Technologies ◽  
Vascular System ◽  
Current Knowledge ◽  
Lymphatic Vessels ◽  
Oral Agents ◽  
Lymphatic Network ◽  
New Generation ◽  
Lymphatic Route

While oral agents have been the gold standard for cardiovascular disease therapy, the new generation of treatments is switching to other administration options that offer reduced dosing frequency and more efficacy. The lymphatic network is a unidirectional and low-pressure vascular system that is responsible for the absorption of interstitial fluids, molecules, and cells from the peripheral tissue, including the skin and the intestines. Targeting the lymphatic route for drug delivery employing traditional or new technologies and drug formulations is exponentially gaining attention in the quest to avoid the hepatic first-pass effect. The present review will give an overview of the current knowledge on the involvement of the lymphatic vessels in drug delivery in the context of cardiovascular disease.

scholarly journals Calcium Mobilization in Endothelial Cell Functions

2019 ◽  
Vol 20 (18) ◽  
pp. 4525 ◽  
Author(s):  
Antonio Filippini ◽  
Antonella D’Amore ◽  
Alessio D’Alessio
Keyword(s):  
Vascular System ◽  
Lymphatic Vessels ◽  
Basal Membrane ◽  
Cell Junctions ◽  
Cellular Mechanisms ◽  
Cell Functions ◽  
Innermost Layer ◽  
Health And Disease ◽  
Membrane Bound

Endothelial cells (ECs) constitute the innermost layer that lines all blood vessels from the larger arteries and veins to the smallest capillaries, including the lymphatic vessels. Despite the histological classification of endothelium of a simple epithelium and its homogeneous morphological appearance throughout the vascular system, ECs, instead, are extremely heterogeneous both structurally and functionally. The different arrangement of cell junctions between ECs and the local organization of the basal membrane generate different type of endothelium with different permeability features and functions. Continuous, fenestrated and discontinuous endothelia are distributed based on the specific function carried out by the organs. It is thought that a large number ECs functions and their responses to extracellular cues depend on changes in intracellular concentrations of calcium ion ([Ca2+]i). The extremely complex calcium machinery includes plasma membrane bound channels as well as intracellular receptors distributed in distinct cytosolic compartments that act jointly to maintain a physiological [Ca2+]i, which is crucial for triggering many cellular mechanisms. Here, we first survey the overall notions related to intracellular Ca2+ mobilization and later highlight the involvement of this second messenger in crucial ECs functions with the aim at stimulating further investigation that link Ca2+ mobilization to ECs in health and disease.

scholarly journals Interaction with the host: the role of fibronectin and extracellular matrix proteins in the adhesion of Gram-negative bacteria

2019 ◽  
Vol 209 (3) ◽  
pp. 277-299 ◽  
Author(s):  
Diana J. Vaca ◽  
Arno Thibau ◽  
Monika Schütz ◽  
Peter Kraiczy ◽  
Lotta Happonen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Outer Membrane Proteins ◽  
Basement Membranes ◽  
Host Cells ◽  
Host Immune System ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Ecm Proteins

AbstractThe capacity of pathogenic microorganisms to adhere to host cells and avoid clearance by the host immune system is the initial and most decisive step leading to infections. Bacteria have developed different strategies to attach to diverse host surface structures. One important strategy is the adhesion to extracellular matrix (ECM) proteins (e.g., collagen, fibronectin, laminin) that are highly abundant in connective tissue and basement membranes. Gram-negative bacteria express variable outer membrane proteins (adhesins) to attach to the host and to initiate the process of infection. Understanding the underlying molecular mechanisms of bacterial adhesion is a prerequisite for targeting this interaction by “anti-ligands” to prevent colonization or infection of the host. Future development of such “anti-ligands” (specifically interfering with bacteria-host matrix interactions) might result in the development of a new class of anti-infective drugs for the therapy of infections caused by multidrug-resistant Gram-negative bacteria. This review summarizes our current knowledge about the manifold interactions of adhesins expressed by Gram-negative bacteria with ECM proteins and the use of this information for the generation of novel therapeutic antivirulence strategies.

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