scholarly journals Vascular Injury Changes Topology of Vessel Network to Adapt to Partition of Blood Flow for New Arteriovenous Specification

2020 ◽  
Author(s):  
Kyung In Baek ◽  
Shyr-Shea Chang ◽  
Chih-Chiang Chang ◽  
Mehrdad Roustei ◽  
Yichen Ding ◽  
...  
Keyword(s):  
Blood Flow ◽  
Endothelial Cell Proliferation ◽  
Loss Of Function ◽  
Vascular Networks ◽  
Loop Formation ◽  
Zebrafish Model ◽  
Cardinal Vein ◽  
Segmental Artery ◽  
Vascular Regeneration ◽  
Organ Systems

AbstractWithin vascular networks, wall shear stress (WSS) modulates endothelial cell proliferation and arteriovenous specification. Mechano-responsive signaling pathways enable vessels within a connected network to structurally adapt to properly partition blood flow between different parts of organ systems. Here, we study vascular regeneration in a zebrafish model system, performing tail amputation of the Dorsal Aorta (DA)-Posterior Cardinal Vein (PCV) embryonic circulatory loop (ECL) at 3 days post fertilization (dpf). Following severing the ECL, the topology of the micro-circular network is reorganized to engender local increase in blood flow and peak WSS in the closest Segmental Artery (SeA) to the amputation site. Remodeling of this artery increases its radius, and blood flow. These hemodynamic WSS cues activate post-angiogenic Notch-ephrinb2 signaling to guide network reconnection and restore microcirculation. Gain- and loss-of-function analyses of Notch and ephrinb2 pathways, manipulations of WSS by modulating myocardial contractility and blood viscosity directly implicate that hemodynamically activated post-angiogenic Notch-ephrinb2 signaling guides network reconnection and restore microcirculation. Taken together, amputation of the DA-PCV loop induces changes in microvascular topology to partition blood flow and increase WSS-mediated Notch-ephrinb2 pathway, driving the new DLAV-PCV loop formation for restoring local microcirculation.

scholarly journals Pharmacological Restoration of Visual Function in a Zebrafish Model of von-Hippel Lindau Disease

2018 ◽  
Author(s):  
Rebecca Ward ◽  
Kayleigh Slater ◽  
Zaheer Ali ◽  
Alison L Reynolds ◽  
Lasse D Jensen ◽  
...  
Keyword(s):  
Visual Function ◽  
Vision Loss ◽  
Kinase Inhibitor ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Zebrafish Model ◽  
Von Hippel Lindau ◽  
Organ Systems ◽  
Vhl Disease

AbstractVon Hippel-Lindau (VHL) syndrome is rare, autosomal dominant disorder, characterized by hypervascularised tumour formation in multiple organ systems. Vision loss associated with retinal capillary hemangioblastomas remains one of the earliest complications of VHL disease. The mortality ofVhl-/-micein uterorestricted modelling of VHL disease in this mammalian model. Zebrafish harbouring a recessive germline mutation in thevhlgene represent a viable, alterative vertebrate model to investigate associated ocularloss-of-functionphenotypes. Previous studies reported neovascularization of the brain, eye and trunk together with odema in thevhl-/-zebrafish eye. In this study, we demonstratevhl-/-zebrafish almost entirely lack visual function. Furthermore, hyaloid vasculature networks in thevhl-/-eye are improperly formed and this phenotype is concomitant with development of an ectopic intraretinal vasculature. Sunitinib, a multi tyrosine kinase inhibitor, market authorised for cancer, reversed the ocular behavioural and morphological phenotypes observed invhl-/-zebrafish. We conclude that the zebrafishvhlgene contributes to the endogenous molecular barrier that prevents development of intraretinal vasculature and that sunitinib can improve visual function and hyaloid vessel patterning while reducing abnormally formed ectopic intraretinal and choroidal vessels invhl-/-zebrafish.

scholarly journals ID: 1013 ETV-2 activated proliferation of endothelial cells and attenuated acute hindlimb ischemia in mice

2017 ◽  
Vol 4 (S) ◽  
pp. 87
Author(s):  
Phuc Van Pham ◽  
Ngoc Bich Vu ◽  
Hoa Trong Nguyen ◽  
Thuy Thi-Thanh Dao ◽  
Ha Thi-Ngan Le ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Endothelial Cells ◽  
Blood Flow ◽  
Viral Vector ◽  
Endothelial Cell Proliferation ◽  
Hindlimb Ischemia ◽  
Blood Oxygen Saturation ◽  
Oxygen Saturation Level ◽  
Vascular Regeneration

Ischemia is the reduction of blood flow to tissues by injury of blood vessels. Depending on the sites of tissues and grade of ischemia, ischemia can cause many serious complications. This study aimed to evaluate the effects of the E-twenty six (ETS) factor Ets variant 2 (ETV2) gene expression in angiogenesis and the effect of ETV2 gene therapy in a mouse model of hindlimb ischemia. The role of ETV2 on endothelial cell proliferation was evaluated in vitro. Knockdown of ETV2 expression was done using short hairpin RNA (shRNA) lentiviral viral particles. The ETV2 viral vector was injected into the skeletal muscles at the ligated and burned sites of the hindlimb and evaluated for its efficacy as a gene therapy modality for ischemia. Vascular regeneration in mice was indirectly evaluated by changes in mouse survival, necrotic grades of the leg, normal blood oxygen saturation level (SpO2), and blood flow by trypan blue injection assay. Preliminary data showed that ETV2 expression played a role in angiogenesis of endothelial cells. ETV2 overexpression could trigger and stimulate proliferation of skeletal endothelial cells. In vivo knockdown of ETV2 expression inhibited the auto-recovery of ischemic hindlimb, while overexpression of ETV2 helped to rescue leg loss and reduce necrosis, significantly improving angiogenesis in hindlimb ischemia. Our findings demonstrate that ETV2 gene therapy is a potentially effective modality for vascular regeneration.

scholarly journals Computational Simulations of the 4-D Micro-Circulatory Network in Zebrafish Tail Amputation and Regeneration

2021 ◽  
Author(s):  
Mehrdad Roustaei ◽  
Kyung In Baek ◽  
Zhaoqiang Wang ◽  
Susana Cavallero ◽  
Sandro Satta ◽  
...  
Keyword(s):  
Flow Rate ◽  
Cfd Simulation ◽  
Fluorescent Protein ◽  
Cfd Modeling ◽  
Endothelial Lining ◽  
Zebrafish Model ◽  
Cardinal Vein ◽  
Vascular Regeneration ◽  
Computational Fluid Dynamics Cfd ◽  
Green Fluorescent

AbstractWall shear stress (WSS) in the micro-vasculature contributes to biomechanical cues that regulate mechanotransduction underlying vascular development, regeneration, and homeostasis. We hereby elucidate the interplay between hemodynamic shear forces and luminal remodeling in response to vascular injury and regeneration in the zebrafish model of tail amputation. Using the transgenic Tg(fli1:eGFP; Gata1:ds-red) line, we were able to track the enhanced green-fluorescent protein (eGFP)-labeled endothelial lining of the 3-D microvasculature for post-image segmentation and reconstruction of fluid domain for computational fluid dynamics (CFD) simulation. At 1 day post amputation (dpa), dorsal aorta (DA) and posterior cardinal vein (PCV) were severed, and vasoconstriction developed in the dorsal longitudinal anastomotic vessel (DLAV) with a concomitant increase in WSS in the segmental vessels (SV) proximal to the amputation site and a decrease in WSS in SVs distal to amputation. Simultaneously, we observed angiogenesis commencing at the tips of the amputated DLAV and PCV where WSS was minimal in the absence of blood flow. At 2 dpa, vasodilation occurred in a pair of SVs proximal to amputation, resulting in increased flow rate and WSS, whereas in the SVs distal to amputation, WSS normalized to the baseline. At 3 dpa, the flow rate in the arterial SV proximal to amputation continued to rise and merged with DLAV that formed a new loop with PCV. Thus, our CFD modeling uncovered a well-coordinated micro-vascular adaptation process following tail amputation, accompanied by the rise and fall of WSS and dynamic changes in flow rate during vascular regeneration.

Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injuries ◽  
Functional Independence ◽  
Outcome Data ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Sixth Edition ◽  
Organ Systems ◽  
Cord Injury ◽  
Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

scholarly journals Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

2021 ◽  
Vol 22 (12) ◽  
pp. 6497
Author(s):  
Anna Ghilardi ◽  
Alberto Diana ◽  
Renato Bacchetta ◽  
Nadia Santo ◽  
Miriam Ascagni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Hair Cells ◽  
Muscle Fibers ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Developmental Defects ◽  
Inner Ear Development ◽  
Syndromic Hearing Loss

The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

scholarly journals The role of CXCR2 in systemic neovascularization of the mouse lung

2007 ◽  
Vol 103 (2) ◽  
pp. 594-599 ◽  
Author(s):  
Jesús Sánchez ◽  
Aigul Moldobaeva ◽  
Jessica McClintock ◽  
John Jenkins ◽  
Elizabeth Wagner
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Left Lung ◽  
Neutralizing Antibody ◽  
Left Pulmonary Artery ◽  
Endothelial Cell Proliferation ◽  
Antibody Treatment ◽  
Pulmonary Artery Obstruction ◽  
Artery Obstruction ◽  
Deficient Mice

We previously showed increased expression of the ELR+, CXC chemokines in the lung after left pulmonary artery obstruction. These chemokines have been shown in other systems to bind their G protein-coupled receptor, CXCR2, and promote systemic endothelial cell proliferation, migration, and capillary tube formation. In the present study, we blocked CXCR2 in vivo using a neutralizing antibody and also studied mice that were homozygous null for CXCR2. To estimate the extent of neovascularization in this model, we measured systemic blood flow to the left lung 14 days after left pulmonary artery ligation (LPAL). We found blood flow significantly reduced (67% decrease) with neutralizing antibody treatment compared with controls. However, blood flow was not altered in the CXCR2-deficient mice compared with wild-type controls after LPAL. To test for ligand availability, we measured macrophage inflammatory protein (MIP)-2 in lung homogenates after LPAL, because this is the predominant CXC chemokine previously shown to be increased after LPAL ( 22 ). MIP-2 protein was two- to fourfold higher in the left lung relative to the right lung in all treatment groups 4 h after LPAL and this increase did not differ among groups. We speculate that the CXCR2-deficient mice have compensatory mechanisms that mitigate their lack of gene expression and conclude that CXCR2 contributes to chemokine-induced systemic angiogenesis after pulmonary artery obstruction.

scholarly journals Mosaicism in Tuberous Sclerosis Complex: A Case Report, Literature Review, and Original Data from Danish Hospitals

2021 ◽  
pp. 98-105
Author(s):  
Julie Loft Nagel ◽  
Maja Patricia Smerdel ◽  
Lisbeth Birk Møller ◽  
Lotte Andreasen ◽  
Anette Bygum
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Original Data ◽  
Hereditary Disease ◽  
Loss Of Function ◽  
Low Level ◽  
Multiple Organs ◽  
Organ Systems

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disease with hamartomatous growths in multiple organs due to loss-of-function variants in TSC1 or TSC2. In approximately 15% of patients with clinical TSC, no pathogenic variant can be identified, and low-level mosaicism is suggested to be one of the reasons. Mosaicism is well-known in TSC and challenges the molecular genetic diagnosis. The advent of next-generation sequencing has improved the diagnostics in TSC including in patients with mosaicism. The TSC phenotype varies widely, and mosaic patients with TSC are often considered to have a milder phenotype. Here, the authors describe a patient with mosaic TSC with a 10% variant allele fraction and manifestations in three organ systems (skin, eyes, and kidneys). Furthermore, the authors studied existing literature about phenotypic organ manifestations in patients with mosaic TSC. No clear definition of the phenotype of patients with mosaic TSC could be established, but unilateral angiofibromas and the absence of tubers and a subependymal nodule could indicate mosaicism. The case shows that patients with low-level mosaic TSC can have multiple affected organ systems though still a mild clinical picture.

scholarly journals A Zebrafish Model of Myelodysplastic Syndrome Produced throughtet2Genomic Editing

2014 ◽  
Vol 35 (5) ◽  
pp. 789-804 ◽  
Author(s):  
Evisa Gjini ◽  
Marc R. Mansour ◽  
Jeffry D. Sander ◽  
Nadine Moritz ◽  
Ashley T. Nguyen ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Catalytic Domain ◽  
Specific Activity ◽  
Cpg Islands ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

The ten-eleven translocation 2 gene (TET2) encodes a member of the TET family of DNA methylcytosine oxidases that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to initiate the demethylation of DNA within genomic CpG islands. Somatic loss-of-function mutations ofTET2are frequently observed in human myelodysplastic syndrome (MDS), which is a clonal malignancy characterized by dysplastic changes of developing blood cell progenitors, leading to ineffective hematopoiesis. We used genome-editing technology to disrupt the zebrafish Tet2 catalytic domain.tet2m/m(homozygous for the mutation) zebrafish exhibited normal embryonic and larval hematopoiesis but developed progressive clonal myelodysplasia as they aged, culminating in myelodysplastic syndromes (MDS) at 24 months of age, with dysplasia of myeloid progenitor cells and anemia with abnormal circulating erythrocytes. The resultanttet2m/mmutant zebrafish lines show decreased levels of 5hmC in hematopoietic cells of the kidney marrow but not in other cell types, most likely reflecting the ability of other Tet family members to provide this enzymatic activity in nonhematopoietic tissues but not in hematopoietic cells.tet2m/mzebrafish are viable and fertile, providing an ideal model to dissect altered pathways in hematopoietic cells and, for small-molecule screens in embryos, to identify compounds with specific activity againsttet2mutant cells.

Abstract 358: First Trimester Human Umbilical Cord Perivascular Cells (FTM HUCPVCs) Maintain High Expression Levels of Angiogenic Factors and Have Superior Pro-angiogenic Effects on Endothelial Networks When Compared to Term HUCPVCs and BMSCs in an ex-vivo Rat Aortic Ring Assay

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Farwah Iqbal ◽  
Peter Szaraz ◽  
Shlomit Kenigsberg ◽  
Andree Gauthier-Fisher ◽  
Clifford Librach
Keyword(s):  
Ex Vivo ◽  
Human Growth ◽  
Aortic Ring ◽  
Angiogenic Factors ◽  
High Expression ◽  
Loop Formation ◽  
Expression Levels ◽  
Vascular Regeneration ◽  
Aortic Ring Assay ◽  
Qpcr Array

Introduction: Features of an ideal cell type, that would be conducive to vascular regeneration include (1) expression of pro-angiogenic genes (2) secretion of factors that promote developing or regenerating vasculature, and (3) maintenance of pro-angiogenic properties in the microvascular niche. Hypothesis: FTM HUCPVCs, a young rich source of mesenchymal stromal-like cells (MSCs) are ideal candidates for vascular regeneration due to their high expression of pro-angiogenic factors. Methods: The paracrine angiogenic potential of 3 types of MSCs was evaluated and compared using ex vivo tissue culture of rat aortic rings. Aorta sections were embedded into Matrigel™, cells were added to transwell membranes (pore=0.1μm, EBM 2% FBS) and combined with aortic rings (Day 0). Radial network growth and total loop formation were monitored by microscopy. Endothelial networks were quantified by ImageJ TM software. p values were calculated using ANOVA. (N=3 experiments, n=3 replicates). At day 7, the MSCs were isolated from transwells, human cytokine gene expression levels were measured using human growth factor profiler qPCR array (Qiagen, normalizers: GAPDH, βACT). Ct>35 considered negligible. Results: In the transwell aortic ring assay, FTM HUCPVCs induced significantly greater network growths when compared to term HUCPVCs (p≤0.0001), BMSCs (p≤0.0001) and untreated rings (p≤0.05). Quantification of network loop formation showed that FTM HUCPVCs induced greater numbers of closed loops when compared to term HUCPVCs (p≤0.0001), BMSCs (p≤0.0001) and untreated networks (p≤0.0001). Human growth factor qPCR array showed a high expression of angiogenic factors (Ct<25 cycle) both at day0 and day7 of co-culture, including BMP1, GDNF, MDK, NRG1, PDGFc, VEGFa, and VEGFc. Most cytokine expression levels were maintained up to 7 days in co-culture with 1 gene upregulated (BMP6 ΔCt>3), and 3 downregulated genes (FGF19, FGF9, NRTN ΔCt>3) at day 7 when compared to day 1. Conclusion: Compared to older sources of MSCs, FTM HUCPVCs promote developing endothelial networks in vitro via paracrine mechanisms and maintain the high expression of pro-angiogenic factors when cultures with endothelial cells.

scholarly journals Phages as immunomodulators and their promising use as anti-inflammatory agents in a cftr loss-of-function zebrafish model

2020 ◽  
Author(s):  
Marco Cafora ◽  
Alessia Brix ◽  
Francesca Forti ◽  
Nicoletta Loberto ◽  
Massimo Aureli ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Zebrafish Model ◽  
Anti Inflammatory
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