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vessels. BMP [51], Notch [52], and semaphorin3a-neuropilin-1 [53]
are also known to play an important role in valvular development
as additional signaling pathways.
The ephrins and the angiopoietins also contribute to lymphatic
vascular maturation. Faulty expression of ephrinB2 would result
in hyperplasia of the collecting lymphatics and absent valve forma-
tion [54]. EphB4 also has a role in signaling in lymphatic vessel valve
development [55]. Angiopoietin 1 and 2 (Ang1 and Ang2) also par-
ticipate in the maturation of the lymphatic vasculature [56–58]. All
of these developmental events are interrelated and complex. New
molecular participants in the process continue to be identified.
Conclusion
Even 400 years after the rediscovery of the lymphatic system by
Gasparo Aselli, the lymphatic system remained misunderstood as
a secondary vascular system to support the blood vascular system.
However, this has now changed. Our understanding of the lym-
phatic system has significantly advanced over the last two decades,
with many landmark discoveries in lymphatic research, especially
in the areas of cellular and molecular biology of LECs. These new
discoveries have brought to light the molecular control of physiolog-
ical and pathological lymphangiogenesis and subsequently chan-
ged the paradigm to re-evaluate the lymphatic system’s essential
role in the human circulatory system in a brand new way.
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[59] YK H, Detmar M. Prox1, master regulator of the lymphatic vasculature pheno-
type. Cell Tissue Res 2003;314:85–92. Epub 2003 Jul 22.
17Further reading
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CHAPTER
3
Lymphatic pumping
and pathological consequences
of its dysfunction
Matthew Stephens, Pierre-Yves von der Weid
Department of Physiology & Pharmacology, Inflammation Research
Network, Snyder Institute of Infection, Immunity & Inflammation,
University of Calgary, Calgary, AB, Canada
The lymphatic system
The lymphatic system is a unidirectional element of the circula-
tion, which is indispensable in human physiology. Composed of a
network of vessels connecting all tissue and interstitial space within
the body to the cardiovascular circulatory system, the lymphatic
system is composed of blunt-ended initial lymphatic vessels and
smooth muscle-surrounded collecting vessels that drain to lymph
nodes widely distributed around the body. The primary purpose
of the lymphatics is to drain excess fluid in the form of lymph
and in the same breath transport proteins, lipids, and cells
around the body in a tightly orchestrated form of immune surveil-
lance. Without a central pump (such as the heart for blood circula-
tion), the lymphatic system is solely reliant on the intrinsic phasic
contractions of lymphatic muscle and on the extrinsic skeletal force
to propel lymph back toward the thoracic duct and subsequently
back into the circulation. Transporting a substantial volume of inter-
stitial fluid (which can amount to 5–6L/day) means that there
are drastic consequences if the flow is disrupted. Failure to clear
19Lymphatic Structure and Function in Health and Disease
https://doi.org/10.1016/B978-0-12-815645-2.00003-4
Copyright © 2020 Elsevier Inc. All rights reserved.
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lymph results in localized inflammation, lymphedema, hypoxia,
and necrosis caused through stagnation of this protein-rich
interstitial fluid.
The initial lymphatics, also termed terminal, peripheral lymphatics,
or lymphatic capillaries, are composed of a single layer of flattened,
nonfenestrated endothelial cells [1]. Typically, significantly larger
than blood capillaries, initials are commonly asymmetrical in shape
[2–4] and connected to neighboring endothelial cells by button-like
junctions, composed of vascular endothelial (VE)-cadherin and tight
junction proteins including occludin, zonula occludens (ZO)-1,
endothelial cell-selective adhesion molecule (ESAM), claudin-5,
and junctional adhesion molecule-A (JAM-A) [5].
Specialized intestinal lymphatics (lacteals) are responsible for a
vast majority of fat absorption [6]. They are surrounded by mucosal
capillaries in a cagelike lattice, with the base lying just below the
basement membrane of enterocytes, thereby providing a strategi-
cally beneficial position for the drainage of fluid escaping from
the capillaries, as well as absorbed through the mucosa. A pivotal
relationship between fat and lymphatics however may exist beyond
the gut, as fat deposition is a defining clinical characteristic of
lymphedema and a large proportion of the associated swelling is
not only fluid but also lipids. It is therefore an up-and-coming area
of research looking into the role the fat plays in lymphatic dysfunc-
tion and pathogenesis of associated diseases.
The lymph content of the initial lymphatics empties into larger
collecting lymphatics. The most important difference between initial
lymphatics and collectors is the presence of surrounding lymphatic
muscle within the vessel wall, which is responsible for the sponta-
neous contraction of the vessel. The efficiency of these contractions
is promoted by the specific design of the collectors, which are
segmented into lymphatic chambers or lymphangions, thanks to
one-way valves interspersed along the vessels. Constrictions of
the lymphangions propel the lymph in a unidirectional fashion
toward the thoracic duct. Normal lymphatic contractile function
is determined by the intrinsic properties of the lymphatic
muscle and the regulation of pumping. Deficiencies in lymphatic
contractility, barrier function, or valve defects are typical among
pathologies of lymphatic system including inherited and acquired
forms of lymphedema, inflammation, lipedema, obesity, metabolic
20 3. Lymphatic pumping and pathological consequences of its dysfunction
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syndrome, and inflammatory bowel disease. In addition to proteins,
lipids, and antigenic material that it transports, lymph also contains
a resident and transient population of cells. These immune and
stromal cells have the potential to drive, alter, and sustain lymphatic
pumping through the secreted content of cytokines, chemokines,
adipokines, lymphokines, and extracellular matrix molecules.
Measures of these various parameters can be a novel and key indi-
cator to lymphatic health and, by proxy, the surrounding tissue.
Disruption with the flow of lymph within a healthy being can result
in an inflammatory response within the affected tissue, which
otherwise would have occurred within the lymph node. This dem-
onstrates further the importance of correct lymph flow within the
body as the dysfunction can lead to not only fluid imbalance and
accumulation but also aberrant local immune responses.
Spread along the lymphatic vessel network, lymph nodes act as
effector venues for adaptive immunity initiation. The number of
lymph nodes can vary between people, although the current reason
behind the phenomenon and outcomes is still being debated. Within
the GI tract, there are numerous nodes acting as draining basins
from organs or subproportions of the intestine. Subdivided into
three major regions, the lymph node is fed by infiltrating lymph
through one or more collecting afferent lymphatic vessels. These
feed into the subcapsular sinus where recognition of circulating
antigen is primarily done by resident macrophages, before the flow
is diverted toward the medullary sinus where, through the
efferent lymphatic, screened fluid leaves. Lymph distribution is
localized to the lymphatic system via afferent lymphatics, the blood
circulation through HEVs, and the parenchyma, which is divided
into B-cell follicles and T-cell areas that form the cortex and medulla,
respectively. The makeup and structural composition of the lymph
node is essential for the correct distribution and movement of anti-
gen, metabolites, and cells throughout the structure so as to create an
environment conducive for a strong adaptive immune response.
The primary purpose of the lymphatic system is fluid homeostasis.
While blood circulation successfully transports a huge volume of
blood around the body each day, fluid leakage into the tissue space
is not recovered. Retrieval is the lymphatic purpose as around 5 L
of interstitial fluid per day is recovered and recycled back into the cir-
culation. Included within this balancing act is the recovery of essential
21The lymphatic system
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metabolites, the removal of toxins, and a key method of cellular trans-
port. As mentioned earlier, to promote a strong and correct immune
response, antigenic material from pathogens must be transported effi-
ciently to the lymph node for presentation and subsequent adaptive
immune response. Flow is initially generated by a hydrostatic gradi-
ent; however to overcome increasing osmolarity, the lymph must be
physically propelled whether by extrinsic forces such as skeletal con-
traction and respiratory pressures or by the intrinsic lymphatic
pump. It is for that reason that the collecting lymphatic pumping is
a critical feature in the lymphatic system and loss of such can have
substantial consequences explored within this chapter.
Origin and mechanisms of lymphatic pumping
Key to fluid homeostasis, the lymphatic pump is the main driver
of lymph propulsion through the body. Without a central pump,
such as the blood circulation, the lymphatic system relies heavily
on the action of the lymphatic muscle cells surrounding the endothe-
lial layer comprising the collectors. These muscle cells have the
intrinsic ability to spontaneously and rhythmically contract and
relax. The intrinsic mechanism, called lymphatic pumping, is com-
plemented by extrinsic forces provided by skeletal muscle contrac-
tions or respiratory movements, which, by transiently compressing
the lymphatic vessels, help lymph propulsion. Efficient lymph
drainage also depends on the synchronized contraction wave along
the length of the vessel, promoted by the lymphangion compart-
mentalization stability and function of intraluminal valves to pre-
vent backflow by forming a tight pressure seal. Thanks to these
morphological characteristics and the combination of intrinsic and
extrinsic forces, lymph can be transported against a hydrostatic
pressure gradient in most regions of the body for successful clear-
ance and recycling into the circulation.
Electrical activity and pacemaker of the lymphatic muscle
Spontaneous lymphatic pumping is a property of most collectors
and is intrinsic to the vessel wall. Lymphatic contraction in human
and mammals is driven by electrical changes of the muscle mem-
brane potential exemplified by action potentials [7–12].
22 3. Lymphatic pumping and pathological consequences of its dysfunction
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The electrophysiological properties of lymphatic muscle are thus
critical to its contractile function. As in most smooth muscles,
action potentials and constrictions in lymphatics depend heavily
on extracellular Ca
2+
ions and can be inhibited by voltage-gated
Ca
2+
channel blockers dihydropyridines [8,13,14]. Involvement of
the L-type Ca
2+
channel, via its main isoform Cav 1.2, in action
potentials was confirmed in rat, mouse, and human mesenteric
vessels [15–18].
The voltage dependence of L-type Ca
2+
channels and the regular-
ity of the action potentials during lymphatic pumping suggest the
involvement of an electrical event that transiently depolarizes the
muscle membrane potential (pacemaker potential) to a level where
the action potentials can be evoked, leading to calcium entry and
phasic contractions [19,20]. Although the origin of cellular events
involved in the lymphatic pacemaker remains currently unknown,
advancements in lymphatic electrophysiology have allowed a
couple of theories to be proposed.
Pioneer studies by McHale and his team in bovine and then sheep
mesenteric lymphatics showed that the initiation and regularity of
the lymphatic action potential bear time and voltage-gated similar-
ities with that observed in the heart and that a hyperpolarization-
activated inward current with properties similar to the sinoatrial
node “funny” current I
f
(HCN channels) was functionally present
in mesenteric vessels, suggesting that like in the heart, HCN chan-
nels may also underlie the lymphatic pacemaker [9,21,22]. A more
recent study reported the expression of all four HCN channel
isoforms in rat diaphragmatic lymphatics [23]. Importantly, in these
studies, pharmacological inhibitors of HCN channels markedly
decreased but never totally abolished the frequency of spontaneous
constrictions, strongly suggesting that other ion channels are
critically involved. Indeed, other currents known to play a role in
cardiac pacemaking, such as T-type Ca
2+
current, Ca
2+
-activated
Cl
current, and fast voltage-activated Na
+
current, demonstrated
to be expressed in sheep, rat, and human mesenteric lymphatic ves-
sels [15,24,25], have been suggested to also participate to
the lymphatic pacemaking. However, similar to HCN channels,
pharmacological inhibition of these channels led partial or very
limited inhibition of lymphatic pumping, further supporting the
idea that other ion conductances are involved.
23Origin and mechanisms of lymphatic pumping
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