scholarly journals Vasohibin 1 selectively regulates secondary sprouting and lymphangiogenesis in the zebrafish trunk

Development ◽  
2021 ◽  
Vol 148 (4) ◽  
pp. dev194993
Author(s):  
Marta Bastos de Oliveira ◽  
Katja Meier ◽  
Simone Jung ◽  
Eireen Bartels-Klein ◽  
Baptiste Coxam ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Zebrafish Embryo ◽  
Cell Number ◽  
Post Translational Modification ◽  
Cardinal Vein ◽  
Cell Functions ◽  
Cell Divisions ◽  
Posterior Cardinal Vein

ABSTRACTPrevious studies have shown that Vasohibin 1 (Vash1) is stimulated by VEGFs in endothelial cells and that its overexpression interferes with angiogenesis in vivo. Recently, Vash1 was found to mediate tubulin detyrosination, a post-translational modification that is implicated in many cell functions, such as cell division. Here, we used the zebrafish embryo to investigate the cellular and subcellular mechanisms of Vash1 on endothelial microtubules during formation of the trunk vasculature. We show that microtubules within venous-derived secondary sprouts are strongly and selectively detyrosinated in comparison with other endothelial cells, and that this difference is lost upon vash1 knockdown. Vash1 depletion in zebrafish specifically affected secondary sprouting from the posterior cardinal vein, increasing endothelial cell divisions and cell number in the sprouts. We show that altering secondary sprout numbers and structure upon Vash1 depletion leads to defective lymphatic vessel formation and ectopic lymphatic progenitor specification in the zebrafish trunk.

scholarly journals Vasohibin-1 mediated tubulin detyrosination selectively regulates secondary sprouting and lymphangiogenesis in the zebrafish trunk

2020 ◽  
Author(s):  
Bastos de Oliveira Marta ◽  
Meier Katja ◽  
Coxam Baptiste ◽  
Geudens Ilse ◽  
Jung Simone ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Zebrafish Embryo ◽  
Lymphatic Vessels ◽  
Post Translational Modification ◽  
Cardinal Vein ◽  
Subsequent Formation ◽  
Cell Functions ◽  
Cell Divisions ◽  
Posterior Cardinal Vein

ABSTRACTPrevious studies have shown that Vasohibin-1 (Vash-1) is stimulated by VEGFs in endothelial cells and that its overexpression interferes with angiogenesis in vivo. Recently, Vasohibin-1 was found to mediate tubulin detyrosination, a post-translational modification that is implicated in many cell functions, such as cell division. Here we used the zebrafish embryo to investigate the cellular and subcellular mechanisms of Vash-1 on endothelial microtubules during formation of the trunk vasculature. We show that microtubules within venous-derived secondary sprouts are strongly and selectively detyrosinated in comparison with other endothelial cells, and that this difference is lost upon vash-1 knockdown. Vasohibin-1 depletion in zebrafish specifically affected secondary sprouting from the posterior cardinal vein, increasing both the number of sprouts and endothelial cell divisions. We show that altering secondary sprout numbers and structure upon vash-1 depletion leads to a failure in the development and specification of lymphatic vessels of the zebrafish trunk.SUMMARYVasohibin-1 mediated detyrosination of endothelial microtubules is selectively required for adequate behaviour of venous secondary sprouting and subsequent formation of functional lymphatics in the zebrafish trunk.

scholarly journals Therapeutic modulation of RNA-binding protein Rbm38 facilitates re-endothelialization after arterial injury

2019 ◽  
Vol 115 (12) ◽  
pp. 1804-1810 ◽  
Author(s):  
Kristina Sonnenschein ◽  
Jan Fiedler ◽  
Angelika Pfanne ◽  
Annette Just ◽  
Saskia Mitzka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Balloon Angioplasty ◽  
Carotid Arteries ◽  
Rna Binding ◽  
Luciferase Reporter ◽  
Binding Motif ◽  
Cell Functions ◽  
Endothelial Regeneration

Abstract Aims Delayed re-endothelialization after balloon angioplasty in patients with coronary or peripheral artery disease impairs vascular healing and leads to neointimal proliferation. In the present study, we examined the effect of RNA-binding motif protein 38 (Rbm38) during re-endothelialization in a murine model of experimental vascular injury. Methods and results Left common carotid arteries of C57BL/6 mice were electrically denudated and endothelial regeneration was evaluated. Profiling of RNA-binding proteins revealed dysregulated expression of Rbm38 in the denudated and regenerated areas. We next tested the importance of Rbm38 in human umbilical vein endothelial cells (HUVECS) and analysed its effects on cellular proliferation, migration and apoptosis. Rbm38 silencing in vitro demonstrated important beneficial functional effects on migratory capacity and proliferation of endothelial cells. In vivo, local silencing of Rbm38 also improved re-endothelialization of denuded carotid arteries. Luciferase reporter assay identified miR-98 and let-7f to regulate Rbm38 and the positive proliferative properties of Rbm38 silencing in vitro and in vivo were mimicked by therapeutic overexpression of these miRNAs. Conclusion The present data identified Rbm38 as an important factor of the regulation of various endothelial cell functions. Local inhibition of Rbm38 as well as overexpression of the upstream regulators miR-98 and let-7f improved endothelial regeneration in vivo and thus may be a novel therapeutic entry point to avoid endothelial damage after balloon angioplasty.

I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4039-4045
Author(s):  
Giovanni Bernardini ◽  
Gaia Spinetti ◽  
Domenico Ribatti ◽  
Grazia Camarda ◽  
Lucia Morbidelli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Rnase Protection Assay ◽  
Chorioallantoic Membrane ◽  
Rnase Protection ◽  
Cc Chemokine ◽  
Cell Functions

Several chemokines have been shown to act as angiogenic molecules or to modulate the activity of growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor (VEGF). The detection of the CC chemokine receptor (CCR) 8 message in human umbilical vein endothelial cells (HUVECs) by reverse transcription– polymerase chain reaction (RT-PCR) and RNase protection assay (RPA), prompted us to investigate the potential role exerted by the CC chemokine I-309, a known ligand of such receptor, in both in vitro and in vivo angiogenesis assays. We show here that I-309 binds to endothelial cells, stimulates chemotaxis and invasion of these cells, and enhances HUVEC differentiation into capillary-like structures in an in vitro Matrigel assay. Furthermore, I-309 is an inducer of angiogenesis in vivo in both the rabbit cornea and the chick chorioallantoic membrane assay (CAM).

I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4039-4045 ◽  
Author(s):  
Giovanni Bernardini ◽  
Gaia Spinetti ◽  
Domenico Ribatti ◽  
Grazia Camarda ◽  
Lucia Morbidelli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Rnase Protection Assay ◽  
Chorioallantoic Membrane ◽  
Rnase Protection ◽  
Cc Chemokine ◽  
Cell Functions

Abstract Several chemokines have been shown to act as angiogenic molecules or to modulate the activity of growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor (VEGF). The detection of the CC chemokine receptor (CCR) 8 message in human umbilical vein endothelial cells (HUVECs) by reverse transcription– polymerase chain reaction (RT-PCR) and RNase protection assay (RPA), prompted us to investigate the potential role exerted by the CC chemokine I-309, a known ligand of such receptor, in both in vitro and in vivo angiogenesis assays. We show here that I-309 binds to endothelial cells, stimulates chemotaxis and invasion of these cells, and enhances HUVEC differentiation into capillary-like structures in an in vitro Matrigel assay. Furthermore, I-309 is an inducer of angiogenesis in vivo in both the rabbit cornea and the chick chorioallantoic membrane assay (CAM).

scholarly journals Liprin β1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 906-909 ◽  
Author(s):  
Camilla Norrmén ◽  
Wouter Vandevelde ◽  
Annelii Ny ◽  
Pipsa Saharinen ◽  
Massimiliano Gentile ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Lipid Absorption ◽  
Tissue Fluid ◽  
Lymphatic Endothelial Cells ◽  
Isolation And Characterization ◽  
Lymphatic Vasculature ◽  
Vessel Integrity

Abstract The lymphatic vasculature is important for the regulation of tissue fluid homeostasis, immune response, and lipid absorption, and the development of in vitro models should allow for a better understanding of the mechanisms regulating lymphatic vascular growth, repair, and function. Here we report isolation and characterization of lymphatic endothelial cells from human intestine and show that intestinal lymphatic endothelial cells have a related but distinct gene expression profile from human dermal lymphatic endothelial cells. Furthermore, we identify liprin β1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, as highly expressed in intestinal lymphatic endothelial cells in vitro and lymphatic vasculature in vivo, and show that it plays an important role in the maintenance of lymphatic vessel integrity in Xenopus tadpoles.

Dual role for TWEAK in angiogenic regulation

2002 ◽  
Vol 115 (2) ◽  
pp. 267-274 ◽  
Author(s):  
Aniela Jakubowski ◽  
Beth Browning ◽  
Matvey Lukashev ◽  
Irene Sizing ◽  
Jeffrey S. Thompson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Cell Types ◽  
Dual Role ◽  
Epithelial Tumor ◽  
Potent Inducer ◽  
Angiogenic Potential ◽  
Cell Functions

Angiogenic regulators modulate endothelial cell functions, including proliferation, migration, secretion, and adhesion, through their action on endothelial cells or other cell types. TWEAK, a novel member of the tumor necrosis factor family, appears to be a pro-angiogenic agent on the basis of previous studies demonstrating its ability to induce interleukin-8 production by epithelial tumor lines, stimulate proliferation of human vascular cell types and neovascularization in rat corneas. Here, we further characterized the angiogenic potential of TWEAK, revealing a dual role for TWEAK as an angiogenic regulator. We demonstrate that TWEAK is a potent inducer of endothelial cell survival and cooperates with basic fibroblast growth factor to induce the proliferation and migration of human endothelial cells and morphogenesis of capillary lumens. In contrast, TWEAK antagonizes the morphogenic response of endothelial cells to vascular endothelial growth factor (VEGF) without inhibiting VEGF-induced survival or proliferation. Thus, our observations suggest that TWEAK may differentially regulate microvascular growth, remodeling and/or maintenance in vivo, depending upon the angiogenic context.

Inhibition of Pathological Retinal Neovascularization by α-Defensins.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3678-3678
Author(s):  
Triantafyllos Chavakis ◽  
Khalil Bdeir ◽  
Douglas B. Cines ◽  
Franz Fogt ◽  
Yasmina Bdeir ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Permeability ◽  
Inhibitory Effect ◽  
Retinal Neovascularization ◽  
Cell Functions ◽  
Extracellular Matrix Components ◽  
Proliferative Retinopathies ◽  
Adhesive Interactions

Abstract Proliferative retinopathies, such as those complicating prematurity and diabetes, are major causes of blindness. A prominent feature of these retinopathies is excessive neovascularization, which is orchestrated by the hypoxia-induced vascular endothelial growth factor (VEGF) stimulating endothelial cells, and the integrin-mediated adhesive interactions of endothelial cells with extracellular matrix components like fibronectin (FN). Recently, we demonstrated that α-defensins interfere with α5β1-FN interactions and dependent endothelial cell functions (FASEB J., 2004, 18:1306–8). Here, α-defensins were studied in hypoxia-induced proliferative retinopathy. In vitro, α-defensins specifically inhibited α5β1-integrin dependent migration of bovine retinal endothelial cells (BREC) to FN, attenuated the VEGF-stimulated increase in endothelial permeability, and blocked BREC proliferation and capillary sprout formation in three-dimensional fibrin-matrices. An upregulation of β1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxia-induced retinal angiogenesis. Systemic and ocular administration of α-defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of α5β1-blocking antibody. α-defensins were detected in human diabetic retinas but were absent in retinas of eyes removed because of trauma. Together, these data show that α-defensins inhibit pathological retinal neovascularization in vivo and may provide a clinically efficient strategy against proliferative retinopathies.

Abstract 317: Endoplasmic Reticulum Stress Alters the Localization of the Prolyl Hydroxylase Ogfod1 in Adult Mouse Cardiomyocytes

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Michael Harris ◽  
Leslie Kennedy ◽  
Junhui Sun ◽  
Matthew Cockman ◽  
Peter Ratcliffe ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Nuclear Space ◽  
Post Translational Modification ◽  
Cell Functions ◽  
Adult Cardiomyocytes ◽  
Function Change ◽  
Prolyl Hydroxylation ◽  
The Unfolded Protein Response

Prolyl hydroxylation is a post-translational modification that is known to regulate several key cell functions including translation and protein stability. Enzymes that catalyze prolyl hydroxylation belong to the 2-oxoglutarate- and iron-dependent oxygenase (2OGDO) family. A newly-identified member of the 2OGDO enzyme family, 2-oxoglutarate- and iron-dependent oxygenase domain-containing protein 1 (Ogfod1), catalyzes prolyl hydroxylation of ribosomal protein s23 (Rps23), a component of the 40S ribosome. To establish an in vivo role for Ogfod1, we ablated Ogfod1 in mice and subjected isolated perfused hearts to ischemia and reperfusion and found Ogfod1 ablation to be cardioprotective. The mechanisms by which these changes occur are currently unknown, so we investigated Ogfod1 regulation and mechanisms of cardioprotection. Previous work has shown that Ogfod1-mediated Rps23 prolyl hydroxylation occurs in the nucleus, where ribosomes are assembled. Additionally, Ogfod1 localizes to cytoplasmic stress granules in transformed cells exposed to endoplasmic reticulum (ER) stress. Based on these studies, we tested the hypothesis that Ogfod1 localization, and subsequently its function, change in response to stress. We induced ER stress by treating isolated adult cardiomyocytes with thapsigargin, and monitored Ogfod1 localization using immunofluorescence. Thapsigargin inhibits sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) which activates the unfolded protein response. In the absence of thapsigargin, Ogfod1 localized to the nucleus, peri-nuclear space, cytoplasm, and cell membrane. After stress induction, Ogfod1 nuclear- and perinuclear-localization decreased. This suggests that in murine adult cardiomyocytes subjected to ER stress, Ogfod1 is exported from the nucleus, potentially as a mechanism for down-regulating its activity. As Ogfod1 ablation has been found to be cardioprotective in mice, understanding Ogfod1 localization and regulation in the cardiomyocyte stress response may provide mechanistic insight that will be useful in developing treatments for stressors such as heart failure.

scholarly journals Abnormalities of follicular helper T-cell number and function in Wiskott-Aldrich syndrome

Blood ◽  
2016 ◽  
Vol 127 (25) ◽  
pp. 3180-3191 ◽  
Author(s):  
Xuan Zhang ◽  
Rongxin Dai ◽  
Wenyan Li ◽  
Hongyi Zhao ◽  
Yongjie Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Subset ◽  
Cell Number ◽  
Wiskott Aldrich Syndrome ◽  
Cell Functions ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Bcl6 Expression

Abstract Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most of which have been attributed to defective T-cell functions. T follicular helper (Tfh) cells are the major CD4+ T-cell subset with specialized B-cell helper capabilities. Aberrant Tfh cells activities are involved in immunopathologies such as autoimmunity, immunodeficiencies, and lymphomas. We found that in WAS patients, the number of circulating Tfh cells was significantly reduced due to reduced proliferation and increased apoptosis, and Tfh cells were Th2 and Th17 polarized. The expression of inducible costimulator (ICOS) in circulating Tfh cells was higher in WAS patients than in controls. BCL6 expression was decreased in total CD4+ T and Tfh cells of WAS patients. Mirroring the results in patients, the frequency of Tfh cells in WAS knockout (KO) mice was decreased, as was the frequency of BCL6+ Tfh cells, but the frequency of ICOS+ Tfh cells was increased. Using WAS chimera mice, we found that the number of ICOS+ Tfh cells was decreased in WAS chimera mice, indicating that the increase in ICOS+ Tfh cells in WAS KO mice was cell extrinsic. The data from in vivo CD4+ naive T-cell adoptive transfer mice as well as in vitro coculture of naive B and Tfh cells showed that the defective function of WASp-deficient Tfh cells was T-cell intrinsic. Consistent findings in both WAS patients and WAS KO mice suggested an essential role for WASp in the development and memory response of Tfh cells and that WASp deficiency causes a deficient differentiation defect in Tfh cells by downregulating the transcription level of BCL6.

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