Lymphatic Vessel

Lymphatic Biology

V. Courtney Broaddus MD , in Murray & Nadel's Textbook of Respiratory Medicine , 2022

Pulmonary Lymphatic Markers

Over the past 2 decades, major advances in the study of lymphangiogenesis were made possible by the identification ofmany lymphangiogenic growth factors, includingvascular endothelial growth factor (VEGF)-C and VEGF-D, which signal through their canonical receptorVEGF receptor 3 (VEGFR3) present on the surface of LECs. 22 Importantly, the identification of markers of pulmonary lymphatics allows the pulmonary lymphatics to be distinguished from the blood vasculature and capillary network in the lung. While many of these markers are also expressed by LECs in other organs, the repertoire of markers expressed by LECs varies according to the organ in which they are located. Therefore, careful analysis is required to ensure that pulmonary lymphatics are properly identified. In the mouse lung, two commonly used markers of lymphatic endothelium, lymphatic vessel endothelial hyaluronan receptor and podoplanin, are not specific for pulmonary lymphatics because they are highly expressed by blood endothelial cells and the epithelium, respectively. 23 , 24 Combination of these markers with other more specific lymphatic markers such as PROX1, a transcription factor and master regulator of lymphatic lineage, increase their utility. Expression of VEGFR3 can be used to identify lymphatics in the mouse lung whereas, in the human lung and in other mouse organs, this marker lacks specificity for the lymphatic endothelium. In humans, podoplanin (D2-40 epitope) has good specificity for identifying lymphatic vessels by immunohistochemistry staining. 25 Further complicating the identification of pulmonary lymphatic vessels is the finding that expression of lymphatic markers may change in the setting of lung injury. 26 , 27 Whenever possible, co-staining using two markers of the lymphatic endothelium should be used to ensure proper distinction of these vessels from the blood endothelium. Commonly used markers of the lymphatic endothelium are detailed inTable 7.1.

Cardiovascular System and Lymphatic Vessels1

Lisa M. Miller , Arnon Gal , in Pathologic Basis of Veterinary Disease (Sixth Edition), 2017

Lymphatic Vessels.

Lymphatic vessels are thin-walled, endothelial-lined channels that originate near the capillary beds and serve as a drainage system for returning interstitial tissue fluid and inflammatory cells to the blood. Afferent lymphatic vessels drain lymph into regional lymph nodes, which then filter and provide immunologic surveillance of the lymph, its cells, and the foreign matter it contains. The filtered lymph continues into larger efferent lymphatic vessels, which eventually drain into the caval blood via the thoracic duct. Both lymphatic vessels and veins have valves to prevent backflow of fluid. A more complete description can be found in Chapter 2.

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Lymphatic Pathophysiology

Anton N. Sidawy MD, MPH , in Rutherford's Vascular Surgery and Endovascular Therapy , 2019

Lymphangiogenesis

In contrast to uncontrolled new growth (lymphangiosarcoma), programmed proliferation of lymphatic endothelium with tube formation (lymphangiogenesis) is critical to a host of physiologic and pathologic processes. During the past several decades, since the phenomenon of angiogenesis was first reproduced in endothelial cell and mixed vascular tissue cultures, 93,94 considerable attention has been directed toward furthering understanding of this process, but largely in the context of blood vessel growth (hemangiogenesis). 95,96 The lymphatic counterpart (i.e., lymphangiogenesis) has received scant attention until recently, although lymphatic (re)generation is essential to health, and disorders of lymph flow and lymphatic growth are common, often disfiguring, and sometimes life- and limb-threatening. 95

In now classic studies, Clark and Clark documented the extension of lymphatic capillaries by outgrowth from preexisting lymph vessels in rabbit ear transparent chambers (Fig. 10.10A). 97 Later, Pullinger and Florey emphasized that despite the similar appearance of each vascular endothelium, lymphatics are consistently connected to lymphatics, veins to veins, and arteries to arteries without intermingling (seeFig. 10.10B). 98

After experimental hind limb circumferential skin incision, new lymphatics traverse the integumentary gap by postoperative day 4. By the eighth day, lymphatic continuity is restored anatomically (delineated by distribution of intradermal India ink particles) and physiologically (remission of transient peripheral edema). 99,100 Bellman and Odén meticulously documented, by Thorotrast microlymphangiography, the time course and extent of newly formed lymphatics in circumferential wounds in the rabbit ear, including lymphatic bridging through newly formed scar (seeFig. 10.10C). 101,102 As lymphatics increased in caliber, intraluminal valves and sinuous dilatations appeared. Subsequent studies documented restoration of distinctive ultrastructural features in newly regenerated lymphatic vessels, including characteristic overlapping junctions and Weibel-Palade bodies (storage depots for vWf [factor VIII–related antigen]). 103-105

Like the more than 1 trillion blood vascular endothelial cells that are normally dormant, 106,107 lymphatic endothelial cell turnover is also miniscule. 108 However, with injury, incorporation of tritiated thymidine into proliferating lymphatic endothelium sharply increases. 108 Moreover, fetal lymphatics show greater labeling than do neonatal and adult lymphatics, whereas visceral lymphatic endothelium proliferates more rapidly than does peripheral lymphatic endothelium. 109

Abdominal and Pelvic Anatomy

Luis M. Chiva , Javier Magrina , in Principles of Gynecologic Oncology Surgery, 2018

Lymphatic Drainage

Lymphatic vessels within the renal parenchyma consist of cortical and medullary plexuses that follow the renal vessels to the renal sinus and form several large lymphatic trunks. The renal sinus is the site of numerous communications between lymphatic vessels from the perirenal tissues, renal pelvis, and upper ureter. Initial lymphatic drainage runs to the nodes present at the renal hilum lying close to the renal vein. These nodes form the first station for the lymphatic spread of renal cancer. On the left side, the lymphatic trunks from the renal hilum drain to the paraaortic lymph nodes from the level of the IMA to the diaphragm. Lymphatic vessels from the right kidney drain into the lateral paracaval and interaortocaval nodes.

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Anatomy of the Kidney

Alan S.L. Yu MB, BChir , in Brenner and Rector's The Kidney , 2020

Lymphatics

The renal lymphatic circulation includes capsular, subcapsular, and intrarenal components. 434,435 The subcapsular component consists of a network of lymphatics in the space between the renal capsule and the renal parenchyma. The intrarenal component includes lymphatic capillaries and channels that coalesce and drain via bundles of lymphatic vessels at the hilum of the kidney. Subcapsular lymphatics may drain directly to the lymphatics at the hilum or may communicate with intrarenal lymphatic vessels. Intrarenal lymphatics neighboring the interlobular blood vessels drain into the arcuate lymphatic vessels near the corticomedullary junction, which drain through interlobar lymphatics to hilar lymphatic vessels ( Fig. 2.56). 436

Communications between the capsular lymphatics and intrarenal lymphatics have been described in some animals, such that the lymphatic vessels of the renal capsule drain into subcapsular lymphatic channels, providing continuous lymphatic drainage from the renal capsule, through the cortex, and into the hilar region (Fig. 2.57). In dog kidney, "communicating" and "perforating" lymphatic channels that transverse the renal capsule have been described. 437 In these studies, a small number of communicating lymphatic channels were found, usually associated with an interlobular artery and vein; these lymphatics penetrated the capsule and appeared to represent a connection between the hilar and capsular systems. The perforating lymphatic channel penetrated the capsule alone or in association with a small vein; these channels appeared to represent a primary pathway for lymph drainage from the superficial cortex.

The intrarenal lymphatics represent a small fraction of the renal tissue, with the lymphatic volume density in the cortex ranging from 0.02%–0.37%, depending on the species. 438,439 In normal human, rat, mouse, and pig kidney, the majority of lymphatic capillaries in the renal parenchyma cluster in the adventitia around the interlobular and arcuate arteries (Fig. 2.58), 434,436,440 and in the mouse, they also extend along the afferent arteriole. 440 In most animal species, lymphatic capillaries are rarely found among renal tubules and glomeruli, but in the horse and dog, lymphatics are abundant around glomeruli, 434 and in dog kidney, small lymphatics are found in proximity to proximal and distal tubules. 438,441 Studies of normal human kidney using immunolabeling to detect lymphatics found lymphatic capillaries most commonly in the adventitia surrounding interlobular and arcuate vessels, as in other species 442,443 ; lymphatic capillaries among renal tubules were rare in one study 443 and in another were described as interspersed among renal tubules in the cortex, though they were less common than vascular capillaries and were sporadic near glomeruli. 442 Lymphatics are rarely found in the medulla of healthy kidneys, a finding that is consistent among species. 440,442,444,445

Cholangiocarcinoma

S. DeMorrow , ... G. Alpini , in Pathobiology of Human Disease, 2014

Lymphangiogenesis

New lymphatic vessels are formed in the tumor microenvironment and this correlates with lymphatic metastasis. Lymphangiogenesis is regulated by growth factors similar to those that control angiogenesis. For example, VEGF-C and D are secreted from the tumor and then activate VEGFR-3 on the lymphatic endothelium. Lymphangiogenesis in CCA is still poorly studied; however, it is known that patients with CCA tumors that have low lymphatic vessel density survive longer than patients that have higher lymphatic vessel density. Additionally, NGF expression correlates with VEGF-C overexpression, lymphatic vessel density, and lymph node metastasis, suggesting that NGF plays a role in modulating lymphangiogenesis in CCA tumors.

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Anatomy and Function of the Skin

Y. Gilaberte , ... Á. Juarranz , in Nanoscience in Dermatology, 2016

Dermal Blood and Lymphatic Vessels

Blood and lymphatic vessels fulfill important homeostatic functions such as providing nutrients for the skin and regulating the immunologic processes. In the dermis, the blood vascularization is organized into a deep plexus and a superficial horizontal plexus, with capillaries arising from the latter one [40,41]. The lymphatic vessels also form two plexuses in proximity to the vascular blood system. Branches from the superficial lymphatic vessel plexus extend into the dermal papillae and drain into the larger lymphatic vessels in the lower dermis [42]. While the blood microvasculature is located immediately below the epidermis, the lymphatic vessels reside more deeply within the dermis [43].

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Volume I

Natasha L. Harvey , in Heart Development and Regeneration, 2010

I Introduction

Lymphatic vessels are a vital but often overlooked component of the cardiovascular system. In contrast to blood vessels, lymphatic vessels do not deliver oxygen and nutrients to tissues, but instead collect and return interstitial fluid and protein (lymph) to the bloodstream. In addition, lymphatic vessels provide an important trafficking route for cells of the immune system during immune surveillance and infection, and facilitate the absorption of lipids from the digestive tract. Lymphatic vascular function is critical for both embryonic development and adult homeostasis, reflected by the fact that abnormalities in the growth and development of lymphatic vessels (lymphangiogenesis) are associated with an ever-expanding catalog of human pathologies. Defects in embryonic lymphangiogenesis that result in dysfunctional lymphatic vessels are associated with congenital lymphoedema syndromes, as well as Down, Noonan's and Turner syndromes. It is likely that the most severe disturbances in embryonic lymphatic vascular development are incompatible with life. Aberrant postnatal lymphangiogenesis has recently been associated with inflammatory pathologies including graft rejection, asthma, psoriasis and arthritis, while the stimulation of lymphangiogenesis by tumors has been demonstrated to promote tumor metastasis in mouse models and has been correlated with poor patient prognosis in several types of human cancers. A major focus of lymphatic vascular research is to delineate the mechanisms by which the lymphatic vasculature is constructed, in order to identify opportunities to intervene in this process and thereby develop better treatments of lymphatic vascular diseases. This chapter will focus on what we currently know about the events that initiate and control construction of the lymphatic vasculature during embryonic development, and how these events are recapitulated or go wrong in disease processes.

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Activation of the Immune System

Sachiko Ono , Kenji Kabashima , in Encyclopedia of Immunobiology, 2016

Lymphatic Vessels

The lymphatic vessels of the skin form the upper and lower plexuses. The superficial plexuses are composed of lymphatic vessels without valves. Branches drain vertically from the superficial plexus into larger lymphatic vessels in the lower dermis and the superficial zone of the subcutaneous tissue. These deep collective lymphatic vessels contain numerous valves ( Wang et al., 2014; Kilarski et al., 2013; Figure 3(b)).

The main function of dermal lymphatics is to promote the movement of interstitial fluid and protein molecules back to the circulation. They thereby maintain normal tissue pressure (Aukland and Reed, 1993; Swartz, 2001). In addition, dermal lymphatics are also important for transporting immune cells such as dDCs from the periphery to the LNs. CCL21/CCR7 signaling is considered necessary for this leukocyte trafficking (Randolph et al., 2005; Kilarski et al., 2013). Moreover, dermal lymphatics target LN-resident DCs and lymphatic endothelial cells (LECs) to capture Ags and participate in immune responses, by draining Ags directly from the dermis (Clement et al., 2011).

Dermal lymphatic failure may lead to a number of diseases that are characterized by edema, impaired immunity, and fibrosis. The function of dermal lymphatics in cutaneous inflammation was examined in murine CHS or ultraviolet B irradiation models. A strong reduction in dermal edema was observed in K14-VEGF-C and K14-VEGF-D transgenic mice, both of which had an expanded network of cutaneous lymphatic vessels. Therefore, lymphatic vessel activation seems to limit acute skin inflammation via the promotion of lymph flow from the skin and the reduction of edema formation (Huggenberger et al., 2011). A study using intradermal vaccination with K14-VEGFR-3-Ig transgenic mice, which lack dermal lymphatic vessels but possess intact LNs and otherwise normal lymphatic vasculature, demonstrated reduced Ab production but exacerbated T cell–mediated CHS responses (Thomas et al., 2012). Therefore, dermal lymphatic vessels likely play complex roles in modulating overall immunity.

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Development and Function of Myeloid Subsets

Andrew M. Platt , Gwendalyn J. Randolph , in Advances in Immunology, 2013

1 Structure and Function of the Lymphatic Vasculature

Lymphatic vessels are found in all tissues with the exception of the bone marrow and central nervous system ( Tammela & Alitalo, 2010). The lymphatic system is organized such that absorptive initial lymphatic capillaries with blind-ended termini are positioned in most organs (Schmid-Schonbein, 1990). Lymphatic capillaries consist of a single layer of lymphatic endothelial cells (LECs). They are not uniform in size, but instead range widely in width from 10 to 80   μm in diameter (Fischer et al., 1996; Spiegel et al., 1992). LECs of capillaries express high levels of the membrane glycoprotein lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). LYVE-1 is dispensable for normal lymphatic development and DC mobilization to LNs (Gale et al., 2007), but as a receptor for hyaluronan, it likely participates importantly in the regulation of immunity and inflammation (Jackson, 2009).

The endothelial cells of lymphatic capillaries exhibit an oak leaf shape with overlapping flaps at their border, which account for their absorptive nature (Fig. 2.1; Baluk et al., 2007). These "button-like" junctions between endothelial cells possess the same junctional proteins as junctions between blood endothelial cells, so it is not their molecular composition but rather their organization that distinguishes them (Baluk et al., 2007). We will discuss in the succeeding text the critical organization of these junctions in the promotion of DC entry into lymphatic vessels.

Figure 2.1. A depiction of the journey of DCs from the tissue interstitium to the draining LN through the lymphatic network. After navigation through the extracellular matrix, DCs must traverse the lymphatic basement membrane that contains "pre-formed portals" (white; ~   1–2   μm diameter), commonly associated with CCL21 puncta (in red). DCs must then squeeze through the gaps in the "button-like" junctions (in red) between oak leaf-shaped lymphatic endothelial cells (LECs) before entering into the lumen of the vessel. The gaps between these junctions are 2–3   μm. Once inside, DCs continue to interact with the luminal side of LECs in a process termed "intralymphatic" crawling, likely facilitated by the flat cross section of these vessels (10–80   μm diameter). When DCs reach collecting vessels, the increased diameter (100–220   μm) and flow rate contribute to a 200-fold faster flow through this region compared with the initial capillaries.

As lymphatics extend toward LNs, the initial lymphatic capillaries converge into larger collecting lymphatic vessels (Schmid-Schonbein, 1990). In mice, these vessels express little if any LYVE-1 (Makinen et al., 2005) and the LECs of collecting vessels are spindle-shaped. Their distinct features include luminal valves that ensure unidirectional flow and an organized mural wall composed of specialized muscle cells (Muthuchamy & Zawieja, 2008). Collecting vessels consist of bulb-like segments called lymphangions that, driven by the muscle cells, contract in a coordinated manner so that lymph pushed through one lymphangion is thrust into the next as the valve closes to prevent fluid backflow. Collecting vessels possess an inherent leakiness (Scallan & Huxley, 2010) that means that some of the contents of lymph are lost in transit. In contrast to lymphatic capillaries, the intercellular junctions between LECs of collecting vessels have a "zipper-like" appearance, more closely resembling those between endothelial cells lining blood vessels and are thus not considered to be absorptive (Baluk et al., 2007). Deep collecting lymphatic vessels are embedded in the perinodal adipose tissue, contact the subcapsular sinus of the LN, and transition into smaller terminal lymphatic capillaries that terminate at the LN capsule (Randolph, Angeli, & Swartz, 2005). Lymph and the cells within it then pass through and around the capsule, with different cell types finding distinct positions in which to enter the LN parenchyma—T cells enter the parenchyma after passing along the sinus toward the medulla, but DCs progress to the medulla near the sites along the sinus where they enter the LN (Braun et al., 2011). Lymph exits the LN through the efferent lymphatic vessel with apparent similar properties as the afferent collecting vessel and can travel through several LNs before returning to the blood circulation via the thoracic duct.

When the lymphatic system is defective, there is an accumulation of protein-rich interstitial fluid in the peripheral tissue that drives chronic inflammation. This, in turn, is thought to be linked to fibrosis and impaired immune responses (Lister, Black, Calonje, & Burnand, 1997; Mallon, Powell, Mortimer, & Ryan, 1997; Rockson, 2001), but little is known regarding the sequence of events or causes of adverse changes. Although primary or congenital lymphedema is relatively rare, the condition is profoundly debilitating. Further, secondary or acquired lymphedema is far more common and is particularly frequent during filariasis and following breast cancer surgery in industrialized countries (Harwood & Mortimer, 1995). Although the lymphatic defects during lymphedema clearly lead to fluid accumulation, until recently, how they impact the capacity of DCs to mobilize from the periphery to draining LNs remained unexplored.

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