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Angiogenesis May 2021There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen,... (Review)
Review
There 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.
Topics: Animals; Blood Vessels; Endothelial Cells; Humans; Lymphatic Vessels; Vascular Malformations
PubMed: 33844116
DOI: 10.1007/s10456-021-09785-7 -
American Journal of Physiology. Renal... Dec 2020Similar to other organs, renal lymphatics remove excess fluid, solutes, and macromolecules from the renal interstitium. Given the kidney's unique role in maintaining...
Similar to other organs, renal lymphatics remove excess fluid, solutes, and macromolecules from the renal interstitium. Given the kidney's unique role in maintaining body fluid homeostasis, renal lymphatics may be critical in this process. However, little is known regarding the pathways involved in renal lymphatic vessel function, and there are no studies on the effects of drugs targeting impaired interstitial clearance, such as diuretics. Using pressure myography, we showed that renal lymphatic collecting vessels are sensitive to changes in transmural pressure and have an optimal range of effective pumping. In addition, they are responsive to vasoactive factors known to regulate tone in other lymphatic vessels including prostaglandin E and nitric oxide, and their spontaneous contractility requires Ca and Cl. We also demonstrated that Na-K-2Cl cotransporter Nkcc1, but not Nkcc2, is expressed in extrarenal lymphatic vessels. Furosemide, a loop diuretic that inhibits Na-K-2Cl cotransporters, induced a dose-dependent dilation in lymphatic vessels and decreased the magnitude and frequency of spontaneous contractions, thereby reducing the ability of these vessels to propel lymph. Ethacrynic acid, another loop diuretic, had no effect on vessel tone. These data represent a significant step forward in our understanding of the mechanisms underlying renal lymphatic vessel function and highlight potential off-target effects of furosemide that may exacerbate fluid accumulation in edema-forming conditions.
Topics: Animals; Calcium; Chlorides; Furosemide; Kidney; Lymphatic Vessels; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pressure; Rats; Rats, Sprague-Dawley; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 33103446
DOI: 10.1152/ajprenal.00322.2020 -
Cold Spring Harbor Perspectives in... Mar 2015Blood and lymphatic vessels deliver oxygen and nutrients, remove waste and CO2, and regulate interstitial pressure in tissues and organs. These vessels begin life early... (Review)
Review
Blood and lymphatic vessels deliver oxygen and nutrients, remove waste and CO2, and regulate interstitial pressure in tissues and organs. These vessels begin life early in embryogenesis using transcription factors and signaling pathways that regulate differentiation, morphogenesis, and proliferation. Here we describe how these vessels develop in the mouse embryo, and the signals that are important to their development.
Topics: Animals; Blood Vessels; Cell Differentiation; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Lymphatic Vessels; Mice; Morphogenesis; Signal Transduction
PubMed: 25731762
DOI: 10.1101/cshperspect.a008268 -
Advanced Drug Delivery Reviews Mar 2021The lymphatic system plays critical roles in tissue fluid homeostasis and immunity and has been implicated in the development of many different pathologies, ranging from... (Review)
Review
The lymphatic system plays critical roles in tissue fluid homeostasis and immunity and has been implicated in the development of many different pathologies, ranging from lymphedema, the spread of cancer to chronic inflammation. In this review, we first summarize the state-of-the-art of lymphatic imaging in the clinic and the advantages and disadvantages of these existing techniques. We then detail recent progress on imaging technology, including advancements in tracer design and injection methods, that have allowed visualization of lymphatic vessels with excellent spatial and temporal resolution in preclinical models. Finally, we describe the different approaches to quantifying lymphatic function that are being developed and discuss some emerging topics for lymphatic imaging in the clinic. Continued advancements in lymphatic imaging technology will be critical for the optimization of diagnostic methods for lymphatic disorders and the evaluation of novel therapies targeting the lymphatic system.
Topics: Diagnostic Imaging; Humans; Lymphatic Vessels; Lymphedema
PubMed: 32891679
DOI: 10.1016/j.addr.2020.08.013 -
Cellular & Molecular Immunology Sep 2023The ever-growing research on lymphatic biology has clearly identified lymphatic vessels as key players that maintain human health through their functional roles in... (Review)
Review
The ever-growing research on lymphatic biology has clearly identified lymphatic vessels as key players that maintain human health through their functional roles in tissue fluid homeostasis, immunosurveillance, lipid metabolism and inflammation. It is therefore not surprising that the list of human diseases associated with lymphatic malfunctions has grown larger, including issues beyond lymphedema, a pathology traditionally associated with lymphatic drainage insufficiency. Thus, the discovery of factors and pathways that can promote optimal lymphatic functions may offer new therapeutic options. Accumulating evidence indicates that aside from biochemical factors, biomechanical signals also regulate lymphatic vessel expansion and functions postnatally. Here, we review how mechanical forces induced by fluid shear stress affect the behavior and functions of lymphatic vessels and the mechanisms lymphatic vessels employ to sense and transduce these mechanical cues into biological signals.
Topics: Humans; Lymphatic Vessels; Inflammation; Homeostasis
PubMed: 37264249
DOI: 10.1038/s41423-023-01042-9 -
Trends in Molecular Medicine Oct 2021The lymphatic vasculature is emerging as a multifaceted regulator of tissue homeostasis and regeneration. Lymphatic vessels drain fluid, macromolecules, and immune cells... (Review)
Review
The lymphatic vasculature is emerging as a multifaceted regulator of tissue homeostasis and regeneration. Lymphatic vessels drain fluid, macromolecules, and immune cells from peripheral tissues to lymph nodes (LNs) and the systemic circulation. Their recently uncovered functions extend beyond drainage and include direct modulation of adaptive immunity and paracrine regulation of organ growth. The developmental mechanisms controlling lymphatic vessel growth have been described with increasing precision. It is less clear how the essential functional features of lymphatic vessels are established and maintained. We discuss the mechanisms that maintain lymphatic vessel integrity in adult tissues and control vessel repair and regeneration. This knowledge is crucial for understanding the pathological vessel changes that contribute to disease, and provides an opportunity for therapy development.
Topics: Homeostasis; Humans; Lymphangiogenesis; Lymphatic Vessels
PubMed: 34332911
DOI: 10.1016/j.molmed.2021.07.003 -
Frontiers in Immunology 2019The lymphatic system comprises a network of lymphoid tissues and vessels that drains the extracellular compartment of most tissues. During tumor development, lymphatic... (Review)
Review
The lymphatic system comprises a network of lymphoid tissues and vessels that drains the extracellular compartment of most tissues. During tumor development, lymphatic endothelial cells (LECs) substantially expand in response to VEGFR-3 engagement by VEGF-C produced in the tumor microenvironment, a process known as tumor-associated lymphangiogenesis. Lymphatic drainage from the tumor to the draining lymph nodes consequently increases, powering interstitial flow in the tumor stroma. The ability of a tumor to induce and activate lymphatic growth has been positively correlated with metastasis. Much effort has been made to identify genes responsible for tumor-associated lymphangiogenesis. Inhibition of lymphangiogenesis with soluble VEGFR-3 or with specific monoclonal antibodies decreases tumor spread to LNs in rodent models. Importantly, tumor-associated lymphatics do not only operate as tumor cell transporters but also play critical roles in anti-tumor immunity. Therefore, metastatic as well as primary tumor progression can be affected by manipulating tumor-associated lymphatic remodeling or function. Here, we review and discuss our current knowledge on the contribution of LECs immersed in the tumor microenvironment as immunoregulators, as well as a possible functional remodeling of LECs subsets depending on the organ microenvironment.
Topics: Animals; Endothelial Cells; Humans; Immunomodulation; Lymphangiogenesis; Lymphatic Vessels; Tumor Microenvironment
PubMed: 31024552
DOI: 10.3389/fimmu.2019.00720 -
Immunological Reviews Mar 2022Afferent lymphatics mediate the transport of antigen and leukocytes, especially of dendritic cells (DCs) and T cells, from peripheral tissues to draining lymph nodes... (Review)
Review
Afferent lymphatics mediate the transport of antigen and leukocytes, especially of dendritic cells (DCs) and T cells, from peripheral tissues to draining lymph nodes (dLNs). As such they play important roles in the induction and regulation of adaptive immunity. Over the past 15 years, great advances in our understanding of leukocyte trafficking through afferent lymphatics have been made through time-lapse imaging studies performed in tissue explants and in vivo, allowing to visualize this process with cellular resolution. Intravital imaging has revealed that intralymphatic leukocytes continue to actively migrate once they have entered into lymphatic capillaries, as a consequence of the low flow conditions present in this compartment. In fact, leukocytes spend considerable time migrating, patrolling and interacting with the lymphatic endothelium or with other intralymphatic leukocytes within lymphatic capillaries. Cells typically only start to detach once they arrive in downstream-located collecting vessels, where vessel contractions contribute to enhanced lymph flow. In this review, we will introduce the biology of afferent lymphatic vessels and report on the presumed significance of DC and T cell migration via this route. We will specifically highlight how time-lapse imaging has contributed to the current model of lymphatic trafficking and the emerging notion that - besides transport - lymphatic capillaries exert additional roles in immune modulation.
Topics: Cell Movement; Dendritic Cells; Endothelium, Lymphatic; Humans; Lymph Nodes; Lymphatic Vessels; T-Lymphocytes
PubMed: 34708414
DOI: 10.1111/imr.13030 -
International Journal of Molecular... Jun 2021Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their... (Review)
Review
Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature.
Topics: Animals; Blood Vessels; Bone Morphogenetic Proteins; Humans; Lymphatic Vessels; Signal Transduction
PubMed: 34198654
DOI: 10.3390/ijms22126364 -
Acta Biomaterialia Oct 2021The lymphatic system plays an integral part in regulating immune cell trafficking and the transport of macromolecules. However, its influence on disease progression and... (Review)
Review
The lymphatic system plays an integral part in regulating immune cell trafficking and the transport of macromolecules. However, its influence on disease progression and drug uptake is understood less than that of the vascular system. To bridge this knowledge gap, biomaterials can be used to investigate the lymphatic system and to provide novel understanding into complex disease processes, including cancer metastasis and inflammation. Insight gained from these mechanistic studies can be further used to design innovative biomaterials to modulate the immune system, improve drug delivery, and promote tissue regeneration. This review article focuses on recent advances in (i) biomaterials used for lymphatic vessel formation, (ii) models for studying lymphatic-immune cells interactions, (iii) pharmaceuticals and their interactions with the lymphatic system, (iv) and strategies for drug delivery via the lymphatic system. Finally, several challenges regarding adopting biomaterials for immunomodulation and future perspectives are discussed. STATEMENT OF SIGNIFICANCE: The lymphatic system plays an integral part in regulating immune cell trafficking and the transport of macromolecules. However, its influence on disease progression and drug uptake is understood less than that of the vascular system. This review article focuses on recent progresses in biomaterials to investigate the lymphatic system and to provide novel understanding into complex disease states. Insight gained from these mechanistic studies can be further used to design innovative biomaterials to modulate the immune system, improve drug delivery, and promote tissue regeneration. Finally, a number of challenges in adopting biomaterials for immunomodulation and future perspectives are discussed.
Topics: Biocompatible Materials; Drug Delivery Systems; Lymphangiogenesis; Lymphatic System; Lymphatic Vessels
PubMed: 34118451
DOI: 10.1016/j.actbio.2021.06.006