scholarly journals A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

2015 ◽  
Vol 212 (7) ◽  
pp. 991-999 ◽  
Author(s):  
Aleksanteri Aspelund ◽  
Salli Antila ◽  
Steven T. Proulx ◽  
Tine Veronica Karlsen ◽  
Sinem Karaman ◽  
...  
Keyword(s):  
Subarachnoid Space ◽  
Interstitial Fluid ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Cervical Lymph Nodes ◽  
Brain Interstitial Fluid ◽  
Lymphatic Vasculature ◽  
The Central Nervous System ◽  
Base Of The Skull ◽  
The Brain

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.

Neural glymphatic system: Clinical implications and potential importance of melatonin

2021 ◽  
Vol 4 (4) ◽  
pp. 551-565
Author(s):  
Ryan D Bitar ◽  
Jorge L Torres-Garza ◽  
Russel J Reiter ◽  
William T Phillips
Keyword(s):  
Lymph Nodes ◽  
Subarachnoid Space ◽  
Slow Wave Sleep ◽  
Lymphatic Vessels ◽  
Amyloid Β ◽  
Secretory Product ◽  
Cervical Lymph Nodes ◽  
Waste Products ◽  
Glymphatic System ◽  
The Brain

The central nervous system was thought to lack a lymphatic drainage until the recent discovery of the neural glymphatic system.  This highly specialized waste disposal network includes classical lymphatic vessels in the dura that absorb fluid and metabolic by-products and debris from the underlying cerebrospinal fluid (CSF) in the subarachnoid space. The subarachnoid space is continuous with the Virchow-Robin peri-arterial and peri-vascular spaces which surround the arteries and veins that penetrate into the neural tissue, respectively.  The dural lymphatic vessels exit the cranial vault via an anterior and a posterior route and eventually drain into the deep cervical lymph nodes. Aided by the presence of aquaporin 4 on the perivascular endfeet of astrocytes, nutrients and other molecules enter the brain from peri-arterial spaces and form interstitial fluid (ISF) that baths neurons and glia before being released into peri-venous spaces.  Melatonin, a pineal-derived secretory product which is in much higher concentration in the CSF than in the blood, is believed to follow this route and to clear waste products such as amyloid-β from the interstitial space. The clearance of amyloid-β reportedly occurs especially during slow wave sleep which happens concurrently with highest CSF levels of melatonin.  Experimentally, exogenously-administered melatonin defers amyloid-β buildup in the brain of animals and causes its accumulation in the cervical lymph nodes. Clinically, with increased age CSF melatonin levels decrease markedly, co-incident with neurodegeneration and dementia.  Collectively, these findings suggest a potential association between the loss of melatonin, decreased glymphatic drainage and neurocognitive decline in the elderly.

scholarly journals Lymphatic vascular morphogenesis in development, physiology, and disease

2011 ◽  
Vol 193 (4) ◽  
pp. 607-618 ◽  
Author(s):  
Stefan Schulte-Merker ◽  
Amélie Sabine ◽  
Tatiana V. Petrova
Keyword(s):  
Dietary Fat ◽  
Interstitial Fluid ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Genetically Engineered ◽  
Novel Therapies ◽  
Vascular Morphogenesis ◽  
Pathological Conditions ◽  
Lymphatic Vasculature ◽  
Cell Dissemination

The lymphatic vasculature constitutes a highly specialized part of the vascular system that is essential for the maintenance of interstitial fluid balance, uptake of dietary fat, and immune response. Recently, there has been an increased awareness of the importance of lymphatic vessels in many common pathological conditions, such as tumor cell dissemination and chronic inflammation. Studies of embryonic development and genetically engineered animal models coupled with the discovery of mutations underlying human lymphedema syndromes have contributed to our understanding of mechanisms regulating normal and pathological lymphatic morphogenesis. It is now crucial to use this knowledge for the development of novel therapies for human diseases.

scholarly journals Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS

2021 ◽  
Vol 15 ◽  
Author(s):  
Gianfranco Natale ◽  
Fiona Limanaqi ◽  
Carla L. Busceti ◽  
Federica Mastroiacovo ◽  
Ferdinando Nicoletti ◽  
...  
Keyword(s):  
Interstitial Fluid ◽  
Lymphatic Vessels ◽  
Normal Pressure ◽  
Lymphatic Drainage ◽  
Brain Parenchyma ◽  
Waste Products ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Glymphatic Pathway ◽  
The Brain

The classic concept of the absence of lymphatic vessels in the central nervous system (CNS), suggesting the immune privilege of the brain in spite of its high metabolic rate, was predominant until recent times. On the other hand, this idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Not long ago, an anatomically and functionally discrete paravascular space was revised to provide a pathway for the clearance of molecules drained within the interstitial space. According to this model, CSF enters the brain parenchyma along arterial paravascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous paravascular spaces, thus being removed from the brain. This process includes the participation of perivascular glial cells due to a sieving effect of their end-feet. Such draining space resembles the peripheral lymphatic system, therefore, the term “glymphatic” (glial-lymphatic) pathway has been coined. Specific studies focused on the potential role of the glymphatic pathway in healthy and pathological conditions, including neurodegenerative diseases. This mainly concerns Alzheimer’s disease (AD), as well as hemorrhagic and ischemic neurovascular disorders; other acute degenerative processes, such as normal pressure hydrocephalus or traumatic brain injury are involved as well. Novel morphological and functional investigations also suggested alternative models to drain molecules through perivascular pathways, which enriched our insight of homeostatic processes within neural microenvironment. Under the light of these considerations, the present article aims to discuss recent findings and concepts on nervous lymphatic drainage and blood–brain barrier (BBB) in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.

scholarly journals CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

2021 ◽  
Vol 12 ◽  
Author(s):  
Sofia Pereira das Neves ◽  
Nickoleta Delivanoglou ◽  
Sandro Da Mesquita
Keyword(s):  
Neurological Disorders ◽  
Vascular System ◽  
Growth Factor Signaling ◽  
Cervical Lymph Nodes ◽  
Continuous Drainage ◽  
Future Challenges ◽  
Lymphatic Vasculature ◽  
The Central Nervous System ◽  
Functional Features ◽  
To Come

A genuine and functional lymphatic vascular system is found in the meninges that sheath the central nervous system (CNS). This unexpected (re)discovery led to a reevaluation of CNS fluid and solute drainage mechanisms, neuroimmune interactions and the involvement of meningeal lymphatics in the initiation and progression of neurological disorders. In this manuscript, we provide an overview of the development, morphology and unique functional features of meningeal lymphatics. An outline of the different factors that affect meningeal lymphatic function, such as growth factor signaling and aging, and their impact on the continuous drainage of brain-derived molecules and meningeal immune cells into the cervical lymph nodes is also provided. We also highlight the most recent discoveries about the roles of the CNS-draining lymphatic vasculature in different pathologies that have a strong neuroinflammatory component, including brain trauma, tumors, and aging-associated neurodegenerative diseases like Alzheimer’s and Parkinson’s. Lastly, we provide a critical appraisal of the conundrums, challenges and exciting questions involving the meningeal lymphatic system that ought to be investigated in years to come.

scholarly journals The Role of Lymphatic Marker Prox-1 in Relation to Brain Tumours

2021 ◽  
Vol 65 (4) ◽  
pp. 72-78
Author(s):  
J. Teleky ◽  
J. Király
Keyword(s):  
Brain Tumours ◽  
Current Knowledge ◽  
Treatment Options ◽  
Lymphatic Vessels ◽  
Homeobox Gene ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
The Central Nervous System ◽  
The Brain

Abstract The homeobox gene, Prox-1 is a transcription factor essential for lymphatic development (lymphangiogenesis) during embryogenesis. It also performs different functions in various tissues such as: retina, lens, liver, pancreas and the central nervous system. Intense expression of Prox-1 has been demonstrated in the developing spinal cord and brain. In adulthood its expression continues in the hippocampus and cerebellum. In adult tissues the process of lymphatic vasculature formation is accompanied under certain pathological conditions such as inflammation, tissue repair and tumour growth. Prox-1 expression is typical for lymphatic vessels; thus it belongs to one of the most specific and widely used mammalian lymphatic endothelial marker in the detection of lymphangiogenesis and lymphatic vessel invasion in oncogenesis. It has been shown that Prox-1 is involved in cancer development and progression. It’s tumour suppressive and oncogenic properties are proven in several human cancers, including brain tumours. Among all body cancers the brain tumours represent the most feared tumours with very limited treatment options and a poor diagnosis. The aim of this paper was to show the current knowledge of the gene Prox-1 with an emphasis on brain tumours, especially in gliomas.

scholarly journals The brain’sglymphatic system:physiological anatomy and clinical perspectives

2018 ◽  
Vol 10 (4) ◽  
pp. 94-100 ◽  
Author(s):  
V. N. Nikolenko ◽  
M. V. Oganesyan ◽  
N. N. Yakhno ◽  
E. A. Orlov ◽  
E. E. Porubayeva ◽  
...  
Keyword(s):  
Interstitial Fluid ◽  
Cerebral Arteries ◽  
Lymphatic Vessels ◽  
Circulatory System ◽  
Brain Parenchyma ◽  
Special Role ◽  
Close Link ◽  
New Therapeutic Approaches ◽  
The Central Nervous System ◽  
The Brain

The recently discovered glymphatic system (GS) ensures the efficient clearance of interstitial fluid and soluble compounds from the central nervous system into cerebrospinal fluid (CSF), which compensates for the lack of conventional lymphatic vessels in the brain parenchyma. This unique anatomical and physiological phenomenon had been unknown until 2012. GS lacks inherent proper vessels Р the current of CSF and interstitial fluid is carried out directly inside the arterial walls (the perivascular pathway) or near the walls of the cerebral arteries and veins (the paravascular pathway). Current biorheological technologies could establish a special role of aquaporin-4 in the filtration of CSF and interstitial fluid. The close link between GS and the CSF circulatory system allows the established views on fluid dynamics within the brain to be reconsidered. The discovery of GS can contribute to our understanding of the pathogenesis of increased intracranial pressure and neurodegenerative diseases, as well as to the elaboration of new therapeutic approaches to their treatment.

The perivascular pathways for influx of cerebrospinal fluid are most efficient in the midbrain

2017 ◽  
Vol 131 (22) ◽  
pp. 2745-2752 ◽  
Author(s):  
Howard Dobson ◽  
Matthew MacGregor Sharp ◽  
Richard Cumpsty ◽  
Theodore P. Criswell ◽  
Tyler Wellman ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Cerebrospinal Fluid ◽  
Subarachnoid Space ◽  
Lymphatic Vessels ◽  
Brain Parenchyma ◽  
Basement Membranes ◽  
Post Mortem ◽  
Cervical Lymph Nodes ◽  
The Brain

Although there are no conventional lymphatic vessels in the brain, fluid and solutes drain along basement membranes (BMs) of cerebral capillaries and arteries towards the subarachnoid space and cervical lymph nodes. Convective influx/glymphatic entry of the cerebrospinal fluid (CSF) into the brain parenchyma occurs along the pial-glial BMs of arteries. This project tested the hypotheses that pial-glial BM of arteries are thicker in the midbrain, allowing more glymphatic entry of CSF. The in vivo MRI and PET images were obtained from a 4.2-year-old dog, whereas the post-mortem electron microscopy was performed in a 12-year-old dog. We demonstrated a significant increase in the thickness of the pial-glial BM in the midbrain compared with the same BM in different regions of the brain and an increase in the convective influx of fluid from the subarachnoid space. These results are highly significant for the intrathecal drug delivery into the brain, indicating that the midbrain is better equipped for convective influx/glymphatic entry of the CSF.

Fisiopatología de la hidrocefália idiopática de presión normal (parte 3): sistemaa glinfático

2016 ◽  
Vol 21 (2) ◽  
pp. 28-37
Author(s):  
Oscar Solís-Salgado ◽  
José Luis López-Payares ◽  
Mauricio Ayala-González
Keyword(s):  
Amyloid Beta ◽  
Interstitial Fluid ◽  
Amyloid Β ◽  
Bulk Flow ◽  
Polyethylene Glycols ◽  
Brain Interstitial Fluid ◽  
El Sistema ◽  
Arterial Pulsation ◽  
The Brain

Las vías de drenaje solutos del sistema nervioso central (SNC) participan en el recambio de liquido intersticial con el líquido cefalorraquídeo (LIT-LCR), generando un estado de homeostasis. Las alteraciones dentro de este sistema homeostático afectará la eliminación de solutos del espacio intersticial (EIT) como el péptido βa y proteína tau, los cuales son sustancias neurotóxicas para el SNC. Se han utilizado técnicas experimentales para poder analizar el intercambio LIT-LCR, las cuales revelan que este intercambio tiene una estructura bien organizada. La eliminación de solutos del SNC no tiene una estructura anatómica propiamente, se han descubierto vías de eliminación de solutos a través de marcadores florecentes en el espacio subaracnoideo, cisternas de la base y sistema ventricular que nos permiten observar una serie de vías ampliamente distribuidas en el cerebro. El LCR muestra que tiene una función linfática debido a su recambio con el LIT a lo largo de rutas paravasculares. Estos espacios que rodean la superficie arterial así como los espacios de Virchow-Robin y el pie astrocitico junto con la AQP-4, facilitan la entrada de LCR para-arterial y el aclaramiento de LIT para-venoso dentro del cerebro. El flujo y dirección que toma el LCR por estas estructuras, es conducido por la pulsación arterial. Esta función será la que finalmente llevara a la eliminación de estas sustancias neurotóxicas. En base a la dependencia de este flujo para la eliminación de sustancias se propone que el sistema sea llamado “ la Vía Glinfática”. La bibliografía así como las limitaciones que se encuentran en esta revisión están dadas por la metodología de búsqueda que ha sido realizada principalmente en PubMed utilizando los siguientes términos Mesh: Cerebral Arterial Pulsation, the brain via paravascular, drainage of amyloid-beta, bulk flow of brain interstitial fluid, radiolabeled polyethylene glycols and albumin, amyloid-β, the perivascular astroglial sheath, Brain Glymphatic Transport.

scholarly journals Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Michael RM Harrison ◽  
Xidi Feng ◽  
Guqin Mo ◽  
Antonio Aguayo ◽  
Jessi Villafuerte ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Lymphatic System ◽  
Vascular System ◽  
Heart Function ◽  
Lymphatic Vessels ◽  
Adult Zebrafish ◽  
Heart Patients ◽  
Scar Size ◽  
Lymphatic Vasculature ◽  
Zebrafish Heart

The cardiac lymphatic vascular system and its potentially critical functions in heart patients have been largely underappreciated, in part due to a lack of experimentally accessible systems. We here demonstrate that cardiac lymphatic vessels develop in young adult zebrafish, using coronary arteries to guide their expansion down the ventricle. Mechanistically, we show that in cxcr4a mutants with defective coronary artery development, cardiac lymphatic vessels fail to expand onto the ventricle. In regenerating adult zebrafish hearts the lymphatic vasculature undergoes extensive lymphangiogenesis in response to a cryoinjury. A significant defect in reducing the scar size after cryoinjury is observed in zebrafish with impaired Vegfc/Vegfr3 signaling that fail to develop intact cardiac lymphatic vessels. These results suggest that the cardiac lymphatic system can influence the regenerative potential of the myocardium.

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