Lymph flows from the tissues to the lymph nodes and eventually to the right lymphatic duct or the largest lymphatic vessel in the body, the thoracic duct.
Lymphatic vessels are thin-walled vessels structured like blood vessels, which carry lymph. The lymphatic vessels are lined by endothelial cells and have a thin layer of smooth muscle and adventitia that attach the lymphatic vessels to the surrounding tissue.
Development of embryonic lymphatic vessels
Lymphatic vessels arise from the cardinal vein after establishing and functioning of the cardiovascular system.
Lymphatic vessel development begins in human embryonic weeks 6 to 7 when a distinct subpopulation of endothelial cells in the lateral part of the anterior cardinal veins commits to a lymphatic lineage and sprouts laterally to form the vascular sacs.
The growth of lymphatic vessels from the lymphatic sacs generates the peripheral lymphatic vasculature, followed by the fusion of the separate lymphatic capillary networks and the remodeling and maturation of the lymphatic capillary plexus.
LYVE1, a specific lymphatic endothelial marker, is expressed on a subset of endothelial cells in central veins and is the first indicator of lymphatic involvement.
In adults, the expression of LYVE1 is decreased in the collecting lymph nodes but remains high in the lymphatic capillaries.
PROX1 expression is specific for lymphatic vessels, and in the mouse, Prox1 knockout embryos do not form lymphatic sacs or lymphatic vessels.
Prox1 overexpression in human blood vascular endothelial cells (VEC) negatively regulates human blood vascular specific genes and positively regulates lymphatic endothelial cell (LEC) gene expression.
The signals that lead to the polarized expression of PROX1 are poorly understood. Still, Francois and colleagues showed the face of the homeobox transcription factor SOX18, mutations that lead to the human hypotrichosis-lymphedema-telangiectasia syndrome (OMIM 206823).
It precedes the expression of PROX1 and that there are SOX18 binding sites on the PROX1 promoter, indicating that SOX18 acts upstream of PROX1 when initiating the lymphatic endothelial cell differentiation program.
The VEGFR3 receptor protein kinase is expressed on all endothelial cells early in development but becomes increasingly specific for endothelial cells committed to a lymphatic lineage.
VEGFR3 is activated by VEGF-C and VEGF-D, but during development, the expression of VEGF-C is predominantly in regions where lymphatic vessels develop.
Direct communication between the lymphatic network and the vascular system occurs around 40 days after conception in humans, so lymphatic drainage from the right and left sides of the upper body, which had accumulated in jugular lymphatic sacs bilateral, empties into the ipsilateral jugular veins.
Failure or delay in completing these communications leads to a generalized distortion of lymphatic development called the jugular lymphatic obstruction sequence.
The clinical consequences of edema distal to the obstruction will vary depending on whether and when communication is established. The total absence of communication is lethal.
Jugular sac distention produces, among other findings, a cystic hygroma that causes excessive skin growth on the neck, posterior hairline, and altered hair pattern, and the ears protrude and rotate.
If the jugular sac is not decompressed until the end of fetal development, the baby will have pterygium coli or neck tissue.
Edema of the hands and feet may not fully resolve at birth, and distal development will have permanent effects, such as a predominance of digital whorls and narrow, hyperconvex nails.
Lymphatic vascular function is critical for embryonic development and adult homeostasis, which is reflected in 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 lymphedema syndromes and Down, Noonan, and Turner syndromes.
The most severe alterations in embryonic lymphatic vascular development are likely 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 shown to promote tumor metastasis in murine models and has been correlated with poor patient prognosis in various types of human cancers.
A primary objective of lymphatic vascular research is to delineate how the lymphatic vasculature is built to identify opportunities to intervene in this process and, therefore, develop better treatments for lymphatic vascular diseases.
If the drainage of lymph from the lower quadrants of the fetus is primarily affected, the lymphatic sacs of the ileum distend, and excess skin grows over the lower abdomen. Prenatal resolution can result in a prune belly congenital disability.
Defective lymphatic development has consequences for the cardiovascular system. Peripheral veins tend to be large, presumably due to increased venous return from edematous tissues.
The frequency of left-sided flow defects (e.g., aortic coarctation, bicuspid aortic valve, hypoplastic left heart) is increased, in part due to the space occupied by the distended jugular sacs.
The lymphatic vessels are a vital but often overlooked component of the cardiovascular system. Unlike blood vessels, lymphatic vessels do not deliver oxygen and nutrients to tissues but instead collect and return interstitial fluid and proteins (lymph) to the bloodstream.
In addition, lymphatic vessels provide a vital trafficking route for cells of the immune system during immunological surveillance and infection and facilitate the absorption of lipids from the digestive tract.
Dermatological blood and lymphatic vessels
Blood and lymphatic vessels serve essential homeostatic functions, such as providing nutrients for the skin and regulating immune processes. In the dermis, the blood supply is organized into a deep plexus and a superficial horizontal plexus, with capillaries arising from the latter.
The lymphatic vessels also form two plexuses in the vicinity of the vascular blood system. The superficial lymphatic vascular plexus branches extend into the dermal papillae and drain into the larger lymphatic vessels in the lower dermis.
While the blood microvasculature is located immediately below the epidermis, the lymphatic vessels reside more profound within the dermis.
Structure of the lymphatic vasculature
Lymphatic vessels are found in all tissues except the bone marrow and the central nervous system. The lymphatic system is organized so that absorbent initial lymphatic capillaries with blind ends are placed in most organs.
Lymphatic capillaries consist of a single layer of lymphatic endothelial cells (LECs). They are not uniform but vary widely in width from 10 to 80 µm in diameter.
Capillary lymphatic endothelial cells express high levels of the hyaluronic lymphatic receptor glycoprotein endothelial receptor-1 (LYVE-1).
The glycoprotein membrane-1 is dispensable for normal lymphatic development and dendritic cell mobilization to the lymph nodes. Still, as a receptor for hyaluronan, it is likely to play an essential role in regulating immunity and inflammation.
The endothelial cells of the lymphatic capillaries exhibit an oak leaf shape with overlapping flaps on their edge, which explains their porous nature.
These “button-shaped” junctions between endothelial cells have the same binding proteins as junctions between endothelial cells in the blood, so it is not their molecular composition but their organization that distinguishes them.
The initial lymphatic capillaries converge into larger lymphatic vessels as the lymphatics extend into the lymph nodes. In mice, these vessels express little or no glycoprotein membrane-1 (LYVE-1), and the lymphatic endothelial cells of the collecting vessels are spindle-shaped.
Its distinctive features include luminal valves that ensure unidirectional flow and an organized wall composed of specialized muscle cells.
The collecting vessels consist of bulb-like segments called lymphangitis that, moved by muscle cells, contract in a coordinated fashion so that lymph pushed through one lymphangion is pushed into the next as the valve closes to prevent reflux. of the liquid.
Collecting vessels have an inherent leakage which means that some lymph contents are lost during transit.
Unlike the lymphatic capillaries, the intercellular junctions between the lymphatic endothelial cells of the collecting vessels have a ‘zipper’ appearance, more similar to those between the endothelial cells that line the blood vessels. Therefore, they are not considered absorbent.
Deep-harvesting lymphatic vessels are embedded in perinodal adipose tissue, contact the subcapsular sinus of the lymph node, and pass into smaller terminal lymphatic capillaries that terminate in the lymph node capsule.
The lymph and the cells within pass through and around the capsule, with different types of cells finding different positions in which to enter the ganglion parenchyma:
T cells enter the parenchyma after passing through the sinus into the marrow, but the dendritic cells advance into the marrow near the sites along the sinus where they enter the lymph node.
Lymph exits the lymph node through the efferent lymph vessel with similar properties to the afferent collecting vessel. It can travel through several lymph nodes before returning to the bloodstream through the thoracic duct.
When the lymphatic system is defective, there is an accumulation of protein-rich interstitial fluid in the peripheral tissue that causes chronic inflammation.
This, in turn, is believed to be related to fibrosis and impaired immune response, but little is known about the sequence of events or causes of adverse changes.
Although primary or congenital lymphedema is relatively rare, the condition is profoundly debilitating. In addition, secondary or acquired lymphedema is much more common and is particularly prevalent during filariasis and after breast cancer surgery in industrialized countries.
Although lymphatic defects during lymphedema lead to fluid accumulation, until recently, how they affected the ability of dendritic cells to move from the periphery to the drainage of the lymph nodes remained unexplored.
Pathophysiology of the lymphatic vessels
Lymphatic vessels are endothelial-lined channels that arise from the outlet of veins. Poorly defined basement membranes facilitate the diffusion of proteins and lipids.
The superficial and deep lymphatic vessels travel parallel to the venous system within the extremities. Superficial lymphatics, lacking valves, drain into deep lymphatic vessels with valves below the muscle fascia.
Deep lymphatic vessels travel alongside large subfascial veins. Lymph nodes connect the superficial and deep lymphatic systems. The thoracic duct drains the lower extremities, the left trunk, and the left upper extremity into the left subclavian vein.
The right lymphatic duct empties the head and neck, the right upper limb, and the right chest into the right subclavian vein. Additional lymphoid tissue is found in the gastrointestinal tract, tonsils, spleen, and thymus.
Lymphatics are not present in the brain, bone marrow, cartilage, cornea, central nervous system, interlobar liver, muscle, or tendon.
The lymphatic vasculature has three functions:
- Transport of proteinaceous fluid (lymph).
- Fat absorption.
- Immune defense.
Peripheral lymphatics transport fluid and proteins back to the vascular system from the interstitial space. Muscle contractions, venous pulsations, and variations in intra-abdominal and intrathoracic pressure stimulate proximal lymphatic flow.
Between 2 and 8 L of blood and between 10% and 50% of high molecular weight proteins are returned daily to the venous circulation by the lymphatic system.
The intestinal lymphatics transmit the digested fat (chyle) to the venous circulation through the thoracic duct. Lymphatic tissue provides immune defense by removing and presenting foreign material in the lymph nodes and producing antibodies.
Lymphatic channel or node dysfunction due to malformation or injury causes accumulation of lymph in the superficial interstitial space. Elevated intralymphatic pressure leads to valve incompetence, decreased proximal flow, and subcutaneous fluid collections.
Intravascular protein leakage increases extracellular oncotic pressure and expands interstitial edema. Compensatory mechanisms, such as increased macrophage activity and spontaneous lymphatic-venous shunts, prevent swelling until 80% of lymphatic flow has been reduced.
Once proteinaceous lymphoid fluid accumulates in the interstitial compartment, subsequent inflammation induces fibrosis and further lymphatic injury.
Lymphatic stagnation increases infection after minor trauma due to impaired immune supervision, decreased oxygen supply to the epidermis, and a protein environment favorable for bacterial growth.