scholarly journals MicroRNA-mediated control of developmental lymphangiogenesis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Hyun Min Jung ◽  
Ciara T Hu ◽  
Alexandra M Fister ◽  
Andrew E Davis ◽  
Daniel Castranova ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Small Rna ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Transcriptional Regulators ◽  
Molecular Regulation ◽  
Small Rna Sequencing ◽  
Positive Role ◽  
Lymphatic Development ◽  
Lymphatic Network

The post-transcriptional mechanisms contributing to molecular regulation of developmental lymphangiogenesis and lymphatic network assembly are not well understood. MicroRNAs are important post-transcriptional regulators during development. Here, we use high throughput small RNA sequencing to identify miR-204, a highly conserved microRNA dramatically enriched in lymphatic vs. blood endothelial cells in human and zebrafish. Suppressing miR-204 leads to loss of lymphatic vessels while endothelial overproduction of miR-204 accelerates lymphatic vessel formation, suggesting a critical positive role for this microRNA during developmental lymphangiogenesis. We also identify the NFATC1 transcription factor as a key miR-204 target in human and zebrafish, and show that NFATC1 suppression leads to lymphatic hyperplasia. The loss of lymphatics caused by miR-204 deficiency can be largely rescued by either endothelial autonomous expression of miR-204 or by suppression of NFATC1. Together, our results highlight a miR-204/NFATC1 molecular regulatory axis required for proper lymphatic development.

scholarly journals MicroRNA-mediated control of developmental lymphangiogenesis

2019 ◽  
Author(s):  
Hyun Min Jung ◽  
Ciara Hu ◽  
Alexandra M. Fister ◽  
Andrew E. Davis ◽  
Daniel Castranova ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Molecular Regulation ◽  
Small Rna Sequencing ◽  
Positive Role ◽  
Vessel Formation ◽  
Lymphatic Development ◽  
Lymphatic Network ◽  
Post Transcriptional Regulation

ABSTRACTThe post-transcriptional mechanisms contributing to molecular regulation of developmental lymphangiogenesis and lymphatic network assembly are not well understood. Here, we use high throughput small RNA sequencing to identify miR-204, a highly conserved miRNA dramatically enriched in lymphatic vs. blood endothelial cells, and we demonstrate that this miRNA plays a critical role during lymphatic development. Suppressing miR-204 leads to loss of lymphatic vessel formation, while overproducing miR-204 in lymphatic vessels accelerates lymphatic vessel formation, suggesting a positive role during developmental lymphangiogenesis. We also identify the NFATC1 transcription factor as a key conserved target for post-transcriptional regulation by miR-204 during lymphangiogenesis. While miR-204 suppression leads to loss of lymphatics, knocking down its target NFATC1 leads to lymphatic hyperplasia, and the loss of lymphatics in miR-204-deficient animals can be rescued by NFATC1 knockdown. Together, our results highlight a miR-204/NFATC1 molecular regulatory axis required for proper lymphatic development.

scholarly journals Oxidative Medicine and Cellular Longevity Changes in the Small RNA Expression in Endothelial Cells in Response to Inflammatory Stimulation

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Peixi Liu ◽  
Liuxun Hu ◽  
Yuan Shi ◽  
Yingjun Liu ◽  
Guo Yu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Small Rna ◽  
Small Rnas ◽  
Cerebrovascular Diseases ◽  
Differentially Expressed ◽  
Small Rna Sequencing ◽  
Rna Expression ◽  
Tissue Specific ◽  
Qrt Pcr ◽  
Tnf Α

Objective. Endothelial cell inflammation is a common pathophysiological process in many cardiovascular and cerebrovascular diseases. Small RNA is a kind of short nonprotein coding RNA molecule. Changes in the small RNA expression in endothelial cells have been linked to the development of cardiovascular and cerebrovascular diseases. We investigated and verified differentially expressed small RNAs in endothelial cells in response to inflammatory stimulation. Methods. Primary rat endothelial cells were obtained from Sprague-Dawley rats and treated with 10 ng/ml TNF-α for 24 hours. Small RNA sequencing was used to generate extensive small RNA data. Significantly differentially expressed small RNAs identified in the analysis were further confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Then, we investigated the tissue-specific small RNA expression after RNA extraction from different tissues. Results. Small RNA sequencing demonstrated that 17 miRNAs, 1 piRNA, 10 snoRNAs, and 7 snRNAs were significantly differentially expressed. qRT-PCR identified 3 miRNAs, 2 snoRNAs, and 2 snRNAs with significantly different expression. Analysis of the tissue-specific expression showed that rno-miR-126a-5p was predominantly expressed in the lung, rno-miR-146a-5p in the intestines, and rno-novel-178 in the heart. Rno-piR-017330 was mainly expressed in the muscle. snoR-8966.1 was predominantly expressed in the bone. snoR-6253.1 was mostly expressed in the vessels and bone. snR-29469.1 was mainly expressed in the bone, and snR-85806.1 was predominantly expressed in the vessels and bone. Conclusions. We report for the first time the expression of small RNAs in endothelial cells under inflammatory conditions. TNF-α can regulate the expression of small RNAs in endothelial cells, and their expression is tissue-specific.

scholarly journals ALK1 signaling regulates early postnatal lymphatic vessel development

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1654-1661 ◽  
Author(s):  
Kyle Niessen ◽  
Gu Zhang ◽  
John Brady Ridgway ◽  
Hao Chen ◽  
Minhong Yan
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Vascular Development ◽  
Lymphatic Vessels ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Lymphatic Endothelial Cells ◽  
Multiple Organs ◽  
Lymphatic Development

Abstract In vertebrates, endothelial cells form 2 hierarchical tubular networks, the blood vessels and the lymphatic vessels. Despite the difference in their structure and function and genetic programs that dictate their morphogenesis, common signaling pathways have been recognized that regulate both vascular systems. ALK1 is a member of the transforming growth factor-β type I family of receptors, and compelling genetic evidence suggests its essential role in regulating blood vascular development. Here we report that ALK1 signaling is intimately involved in lymphatic development. Lymphatic endothelial cells express key components of the ALK1 pathway and respond robustly to ALK1 ligand stimulation in vitro. Blockade of ALK1 signaling results in defective lymphatic development in multiple organs of neonatal mice. We find that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling. Furthermore, simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling. Thus, our study reveals a novel aspect of ALK1 signaling in regulating lymphatic development and suggests that targeting ALK1 pathway might provide additional control of lymphangiogenesis in human diseases.

scholarly journals Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation

Blood ◽  
2016 ◽  
Vol 128 (9) ◽  
pp. 1169-1173 ◽  
Author(s):  
John D. Welsh ◽  
Mark L. Kahn ◽  
Daniel T. Sweet
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Lymph Flow ◽  
The Body ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Circulation ◽  
Vessel Maturation

Abstract Aside from the established role for platelets in regulating hemostasis and thrombosis, recent research has revealed a discrete role for platelets in the separation of the blood and lymphatic vascular systems. Platelets are activated by interaction with lymphatic endothelial cells at the lymphovenous junction, the site in the body where the lymphatic system drains into the blood vascular system, resulting in a platelet plug that, with the lymphovenous valve, prevents blood from entering the lymphatic circulation. This process, known as “lymphovenous hemostasis,” is mediated by activation of platelet CLEC-2 receptors by the transmembrane ligand podoplanin expressed by lymphatic endothelial cells. Lymphovenous hemostasis is required for normal lymph flow, and mice deficient in lymphovenous hemostasis exhibit lymphedema and sometimes chylothorax phenotypes indicative of lymphatic insufficiency. Unexpectedly, the loss of lymph flow in these mice causes defects in maturation of collecting lymphatic vessels and lymphatic valve formation, uncovering an important role for fluid flow in driving endothelial cell signaling during development of collecting lymphatics. This article summarizes the current understanding of lymphovenous hemostasis and its effect on lymphatic vessel maturation and synthesizes the outstanding questions in the field, with relationship to human disease.

scholarly journals Smooth muscle–endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation

2012 ◽  
Vol 197 (6) ◽  
pp. 837-849 ◽  
Author(s):  
Sophie Lutter ◽  
Sherry Xie ◽  
Florence Tatin ◽  
Taija Makinen
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Lymphatic Vessel ◽  
System Development ◽  
Lymphatic Vessels ◽  
Cell Communication ◽  
Nervous System Development ◽  
Proteolytic Processing ◽  
Lymphatic Capillary ◽  
Reelin Signaling

Active lymph transport relies on smooth muscle cell (SMC) contractions around collecting lymphatic vessels, yet regulation of lymphatic vessel wall assembly and lymphatic pumping are poorly understood. Here, we identify Reelin, an extracellular matrix glycoprotein previously implicated in central nervous system development, as an important regulator of lymphatic vascular development. Reelin-deficient mice showed abnormal collecting lymphatic vessels, characterized by a reduced number of SMCs, abnormal expression of lymphatic capillary marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and impaired function. Furthermore, we show that SMC recruitment to lymphatic vessels stimulated release and proteolytic processing of endothelium-derived Reelin. Lymphatic endothelial cells in turn responded to Reelin by up-regulating monocyte chemotactic protein 1 (MCP1) expression, which suggests an autocrine mechanism for Reelin-mediated control of endothelial factor expression upstream of SMC recruitment. These results uncover a mechanism by which Reelin signaling is activated by communication between the two cell types of the collecting lymphatic vessels—smooth muscle and endothelial cells—and highlight a hitherto unrecognized and important function for SMCs in lymphatic vessel morphogenesis and function.

scholarly journals The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology

2021 ◽  
Vol 22 (12) ◽  
pp. 6364
Author(s):  
Ljuba C. Ponomarev ◽  
Jakub Ksiazkiewicz ◽  
Michael W. Staring ◽  
Aernout Luttun ◽  
An Zwijsen
Keyword(s):  
Endothelial Cells ◽  
Bone Morphogenetic Proteins ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Vascular Diseases ◽  
Bmp Signaling ◽  
Molecular Heterogeneity ◽  
Active Components ◽  
Surrounding Matrix ◽  
Bmp Pathway

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.

scholarly journals The microRNA miR-132 is a key regulator of lymphatic vascular remodelling

2021 ◽  
Author(s):  
Marc Achen ◽  
Valeria Arcucci ◽  
Musarat Ishaq ◽  
Sally Roufail ◽  
Kate Dredge ◽  
...  
Keyword(s):  
Growth Factors ◽  
Small Rna ◽  
Lymphatic Vessels ◽  
Tube Formation ◽  
Small Rna Sequencing ◽  
Lymphatic Endothelial Cells ◽  
Rna Molecules ◽  
Key Steps

Lymphangiogenesis (growth of new lymphatic vessels), and lymphatic remodelling more broadly, are important for disease progression in cancer, lymphedema and the pulmonary disease lymphangioleiomyomatosis. Multiple molecular pathways which signal for aspects of lymphangiogenesis are known but little is understood about their co-ordinate regulation in lymphatic endothelial cells (LECs). Small RNA molecules co-ordinately regulate complex biological processes, but knowledge about their involvement in lymphangiogenesis is limited. Here we used high-throughput small RNA sequencing of LECs to identify microRNAs (miRs) regulating lymphatic remodelling driven by the lymphangiogenic growth factors VEGF-C and VEGF-D. We identified miR-132 as up-regulated by both growth factors, and demonstrated that inhibiting miR-132 in LECs in vitro blocked cell proliferation and tube formation, key steps in lymphangiogenesis. We showed that miR-132 is expressed in human LECs in vivo in the lymphatics of human breast tumours expressing VEGF-D. Importantly, we demonstrated that inhibiting miR-132 in vivo blocked many aspects of lymphangiogenesis in mice. Finally, we identified mRNAs regulated by miR-132 in LECs, by sequencing after RNA-protein cross-linking and Argonaute immunoprecipitation, which demonstrated how miR-132 co-ordinately regulates signalling pathways in lymphangiogenesis. This study shows miR-132 is a critical regulator of lymphangiogenesis and a potential target for therapeutically manipulating lymphatic remodelling in disease.

scholarly journals Loss of Primary Cilia Protein IFT20 Dysregulates Lymphatic Vessel Patterning in Development and Inflammation

2021 ◽  
Vol 9 ◽  
Author(s):  
Delayna Paulson ◽  
Rebecca Harms ◽  
Cody Ward ◽  
Mackenzie Latterell ◽  
Gregory J. Pazour ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Primary Cilia ◽  
Fluid Shear Stress ◽  
Lymphatic Vessels ◽  
Intraflagellar Transport ◽  
Membrane Receptors ◽  
Lymphatic Endothelial Cells ◽  
Corneal Lymphangiogenesis

Microenvironmental signals produced during development or inflammation stimulate lymphatic endothelial cells to undergo lymphangiogenesis, in which they sprout, proliferate, and migrate to expand the vascular network. Many cell types detect changes in extracellular conditions via primary cilia, microtubule-based cellular protrusions that house specialized membrane receptors and signaling complexes. Primary cilia are critical for receipt of extracellular cues from both ligand-receptor pathways and physical forces such as fluid shear stress. Here, we report the presence of primary cilia on immortalized mouse and primary adult human dermal lymphatic endothelial cells in vitro and on both luminal and abluminal domains of mouse corneal, skin, and mesenteric lymphatic vessels in vivo. The purpose of this study was to determine the effects of disrupting primary cilia on lymphatic vessel patterning during development and inflammation. Intraflagellar transport protein 20 (IFT20) is part of the transport machinery required for ciliary assembly and function. To disrupt primary ciliary signaling, we generated global and lymphatic endothelium-specific IFT20 knockout mouse models and used immunofluorescence microscopy to quantify changes in lymphatic vessel patterning at E16.5 and in adult suture-mediated corneal lymphangiogenesis. Loss of IFT20 during development resulted in edema, increased and more variable lymphatic vessel caliber and branching, as well as red blood cell-filled lymphatics. We used a corneal suture model to determine ciliation status of lymphatic vessels during acute, recurrent, and tumor-associated inflammatory reactions and wound healing. Primary cilia were present on corneal lymphatics during all of the mechanistically distinct lymphatic patterning events of the model and assembled on lymphatic endothelial cells residing at the limbus, stalk, and vessel tip. Lymphatic-specific deletion of IFT20 cell-autonomously exacerbated acute corneal lymphangiogenesis resulting in increased lymphatic vessel density and branching. These data are the first functional studies of primary cilia on lymphatic endothelial cells and reveal a new dimension in regulation of lymphatic vascular biology.

Initial Steps Toward Development of a Lumped-Parameter Model of the Lymphatic Network

2013 ◽  
Author(s):  
Samira Jamalian ◽  
Christopher D. Bertram ◽  
James E. Moore
Keyword(s):  
Blood Circulation ◽  
Lymphatic Vessel ◽  
Lymphatic System ◽  
Lymphatic Vessels ◽  
The Body ◽  
Lumped Parameter Model ◽  
Circulation System ◽  
Blood Circulation System ◽  
Lumped Parameter ◽  
Lymphatic Network

One of the primary functions of the lymphatic system is maintaining fluid and protein balance in the body. The system holds this balance by collecting about four liters of fluid every day from the interstitial space and returning it back to the subclavian vein. In contrast to the blood circulation system that relies on the heart for pumping, there is no central pump in the lymphatic system. Thus, the transport of viscous fluid against gravity and pressure difference occurs by recruiting extrinsic and intrinsic pumping mechanisms. Extrinsic pumping is the transport of lymph due to the movements outside the lymphatic vessel such as the pulse in blood vessels, whereas the intrinsic pumping is transport of lymph by contraction of lymphatic muscle cells embedded in the walls of lymphatic vessels. Similar to the veins, the bi-leaflet valves throughout the lymphatic network prevent backflow. Lymphatic valves are biased open and allow for small amounts of back flow before they completely shut.

scholarly journals Epigenetic priming by Dot1l in lymphatic endothelial progenitors ensures normal lymphatic development and function

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyunjin Yoo ◽  
Young Jae Lee ◽  
Chanhyeok Park ◽  
Dabin Son ◽  
Dong Yoon Choi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessels ◽  
Genetic Studies ◽  
Hematopoietic Stem ◽  
Genetic Ablation ◽  
Multiple Organs ◽  
Expression Of Genes ◽  
Lymphatic Development ◽  
And Function

AbstractProper functioning of the lymphatic system is required for normal immune responses, fluid balance, and lipid reabsorption. Multiple regulatory mechanisms are employed to ensure the correct formation and function of lymphatic vessels; however, the epigenetic modulators and mechanisms involved in this process are poorly understood. Here, we assess the regulatory role of mouse Dot1l, a histone H3 lysine (K) 79 (H3K79) methyltransferase, in lymphatic formation. Genetic ablation of Dot1l in Tie2(+) endothelial cells (ECs), but not in Lyve1(+) or Prox1(+) lymphatic endothelial cells (LECs) or Vav1(+) definitive hematopoietic stem cells, leads to catastrophic lymphatic anomalies, including skin edema, blood–lymphatic mixing, and underdeveloped lymphatic valves and vessels in multiple organs. Remarkably, targeted Dot1l loss in Tie2(+) ECs leads to fully penetrant lymphatic aplasia, whereas Dot1l overexpression in the same cells results in partially hyperplastic lymphatics in the mesentery. Genetic studies reveal that Dot1l functions in c-Kit(+) hemogenic ECs during mesenteric lymphatic formation. Mechanistically, inactivation of Dot1l causes a reduction of both H3K79me2 levels and the expression of genes important for LEC development and function. Thus, our study establishes that Dot1l-mediated epigenetic priming and transcriptional regulation in LEC progenitors safeguard the proper lymphatic development and functioning of lymphatic vessels.

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