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 Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

2019 ◽  
Vol 21 (1) ◽  
pp. 266 ◽  
Author(s):  
Gabriella Schiera ◽  
Carlo Maria Di Liegro ◽  
Italia Di Liegro
Keyword(s):  
Learning And Memory ◽  
Extracellular Vesicles ◽  
Glial Cells ◽  
Information Exchange ◽  
System Development ◽  
Cell Communication ◽  
Nervous System Development ◽  
The Body ◽  
Pathological Conditions ◽  
And Function

Most aspects of nervous system development and function rely on the continuous crosstalk between neurons and the variegated universe of non-neuronal cells surrounding them. The most extraordinary property of this cellular community is its ability to undergo adaptive modifications in response to environmental cues originating from inside or outside the body. Such ability, known as neuronal plasticity, allows long-lasting modifications of the strength, composition and efficacy of the connections between neurons, which constitutes the biochemical base for learning and memory. Nerve cells communicate with each other through both wiring (synaptic) and volume transmission of signals. It is by now clear that glial cells, and in particular astrocytes, also play critical roles in both modes by releasing different kinds of molecules (e.g., D-serine secreted by astrocytes). On the other hand, neurons produce factors that can regulate the activity of glial cells, including their ability to release regulatory molecules. In the last fifteen years it has been demonstrated that both neurons and glial cells release extracellular vesicles (EVs) of different kinds, both in physiologic and pathological conditions. Here we discuss the possible involvement of EVs in the events underlying learning and memory, in both physiologic and pathological conditions.

Abstract 180: The Myristolated Alanine-Rich C Kinase Substrate (MARCKS) Differentially Regulates Proliferation of Vascular Smooth Muscle Cells and Endothelial Cells through Affecting Protein Stability and Proteolytic Processing of the Kinase Interacting with Stathmin (KIS)

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Dan Yu ◽  
Charles Drucker ◽  
Rajabrata Sarkar ◽  
Dudley K Strickland ◽  
Thomas S Monahan
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Smooth Muscle Cells ◽  
Protein Stability ◽  
Muscle Cells ◽  
Cell Types ◽  
Proteolytic Processing ◽  
Functional Domain ◽  
Human Coronary Artery

Objective: Presently, the antiproliferative agents used in drug eluting stents and drug coated balloons inhibit both VSMC and endothelial cell (EC) proliferation, and thus these patients require dual antiplatelet therapy indefinitely. Identification of a VSMC-specific target to prevent proliferation represents a significant unmet clinical need. Previously we found that knockdown of MARCKS arrests VSMC proliferation through a p27 kip1 -dependent mechanism. Interestingly MARCKS knockdown increases EC proliferation. p27 kip1 is phosphorylated by KIS allowing it to exit the nucleus and be degraded. Here we seek to understand how MARCKS influences KIS protein expression in these two cell types. Approach and Results: We performed siRNA-mediated knock down of MARCKS in human coronary artery endothelial cells (CAECs) and human coronary artery smooth muscle cells (CASMCs). MARCKS knockdown did not affect KIS mRNA expression as determined with RT-PCR in either cell type. KIS protein stability was evaluated in the presence of cyclohexamide with Western blot. In CAECs, MARCKS knockdown increased KIS stability, however, in CASMCs, MARCKS knockdown significantly decreased KIS protein stability. In CASMCs, MARCKS knockdown significantly increased KIS ubiquitinization where as in CAECs, MARCKS knockdown decreased KIS ubiquitinization. Interestingly, the well-studied functional domain of MARCKS(ED domain) is not directly involved in KIS regulation. MARCKS mutants (S4G and S4D) rescued proliferation in VSMCs. MARCKS knockdown in vivo in the murine femoral wire injury model resulted in decreased medial bromodeoxyuridine (BrdU) integration and neointima formation. MARCKS knockdown enhanced endothelial barrier function recovery four days after injury as assessed by Evans Blue integration. Conclusions: MARCKS differentially regulates the protein stability and proteolytic processing of KIS in VSMCs and ECs. The differential interaction of MARCKS and KIS likely explains the observed difference in proliferation observed with MARCKS knockdown in these two cell types.

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 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 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.

scholarly journals Embryonic periventricular endothelial cells demonstrate a unique pro-neurodevelopment and anti-inflammatory gene signature

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Franciele Cristina Kipper ◽  
Cleide Angolano ◽  
Ravi Vissapragada ◽  
Mauricio A. Contreras ◽  
Justin Moore ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Neural Progenitor Cells ◽  
Therapeutic Potential ◽  
System Development ◽  
Gene Signature ◽  
Nervous System Development ◽  
Adult Brain ◽  
Barrier Formation ◽  
Canonical Pathways ◽  
Neurovascular Niche

AbstractBrain embryonic periventricular endothelial cells (PVEC) crosstalk with neural progenitor cells (NPC) promoting mutual proliferation, formation of tubular-like structures in the former and maintenance of stemness in the latter. To better characterize this interaction, we conducted a comparative transcriptome analysis of mouse PVEC vs. adult brain endothelial cells (ABEC) in mono-culture or NPC co-culture. We identified > 6000 differentially expressed genes (DEG), regardless of culture condition. PVEC exhibited a 30-fold greater response to NPC than ABEC (411 vs. 13 DEG). Gene Ontology (GO) analysis of DEG that were higher or lower in PVEC vs. ABEC identified “Nervous system development” and “Response to Stress” as the top significantly different biological process, respectively. Enrichment in canonical pathways included HIF1A, FGF/stemness, WNT signaling, interferon signaling and complement. Solute carriers (SLC) and ABC transporters represented an important subset of DEG, underscoring PVEC’s implication in blood–brain barrier formation and maintenance of nutrient-rich/non-toxic environment. Our work characterizes the gene signature of PVEC and their important partnership with NPC, underpinning their unique role in maintaining a healthy neurovascular niche, and in supporting brain development. This information may pave the way for additional studies to explore their therapeutic potential in neuro-degenerative diseases, such as Alzheimer’s and Parkinson’s disease.

scholarly journals Regional Differences in Gene Expression of Proliferating Human Choroidal Endothelial Cells

2021 ◽  
Vol 1 (2) ◽  
pp. 83-100
Author(s):  
Andrew C. Browning ◽  
Eugene P. Halligan ◽  
Elizabeth A. Stewart ◽  
Daniel C. Swan ◽  
Simon J. Cockell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Regional Differences ◽  
System Development ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Nervous System Development ◽  
Site Specific ◽  
Specific Selectivity ◽  
Vascular Beds

Choroidal diseases including inflammation and neovascularization seem to have predilection for different vascular beds. In order to improve our understanding of human macular choroidal angiogenic diseases, we investigate the differences in gene expression between matched human macular and peripheral inner choroidal endothelial cells (CEC) and matched human macular inner and outer CEC. The gene expression profiles of matched, unpassaged human macular and peripheral inner CEC and matched human unpassaged macular inner and outer CEC were conducted using Affymetrix GeneChip arrays. Selected differences in gene expression were validated by real-time-PCR and immunohistochemistry. No differences in probeset expression were demonstrated between inner CECs compared with peripheral inner CECs. In comparison, there was a difference of 1.6% of probesets when matched, unpassaged proliferating human macular inner CEC and macular outer CEC from the same donors were compared. Macular inner CECs demonstrated up-regulation of probesets involved in nervous system development, growth factors, PLVAP, and collagen XVI, while macular outer CECs demonstrated up-regulation of probesets involved in immune function and intracellular signalling. There was a marked homogeneity of human macular and peripheral inner CECs. This suggests that gene expression differences in inner CECs are not responsible for the site specific selectivity of choroidal neovascularisation. Variability was noted, however, in the gene expression of matched macular inner and outer CECs. This could be explained by the differences in the roles and microenvironments of the inner and outer choroid.

scholarly journals Investigating lymphangiogenesis in vitro and in vivo using engineered human lymphatic vessel networks

2021 ◽  
Vol 118 (31) ◽  
pp. e2101931118
Author(s):  
Shira Landau ◽  
Abigail Newman ◽  
Shlomit Edri ◽  
Inbal Michael ◽  
Shahar Ben-Shaul ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Blood Vessels ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cells ◽  
Supporting Cells ◽  
Vessel Formation ◽  
Vessel Networks

The lymphatic system is involved in various biological processes, including fluid transport from the interstitium into the venous circulation, lipid absorption, and immune cell trafficking. Despite its critical role in homeostasis, lymphangiogenesis (lymphatic vessel formation) is less widely studied than its counterpart, angiogenesis (blood vessel formation). Although the incorporation of lymphatic vasculature in engineered tissues or organoids would enable more precise mimicry of native tissue, few studies have focused on creating engineered tissues containing lymphatic vessels. Here, we populated thick collagen sheets with human lymphatic endothelial cells, combined with supporting cells and blood endothelial cells, and examined lymphangiogenesis within the resulting constructs. Our model required just a few days to develop a functional lymphatic vessel network, in contrast to other reported models requiring several weeks. Coculture of lymphatic endothelial cells with the appropriate supporting cells and intact PDGFR-β signaling proved essential for the lymphangiogenesis process. Additionally, subjecting the constructs to cyclic stretch enabled the creation of complex muscle tissue aligned with the lymphatic and blood vessel networks, more precisely biomimicking native tissue. Interestingly, the response of developing lymphatic vessels to tensile forces was different from that of blood vessels; while blood vessels oriented perpendicularly to the stretch direction, lymphatic vessels mostly oriented in parallel to the stretch direction. Implantation of the engineered lymphatic constructs into a mouse abdominal wall muscle resulted in anastomosis between host and implant lymphatic vasculatures, demonstrating the engineered construct's potential functionality in vivo. Overall, this model provides a potential platform for investigating lymphangiogenesis and lymphatic disease mechanisms.

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