scholarly journals Association between erythrocyte dynamics and vessel remodelling in developmental vascular networks

2021 ◽  
Vol 18 (179) ◽  
pp. 20210113
Author(s):  
Qi Zhou ◽  
Tijana Perovic ◽  
Ines Fechner ◽  
Lowell T. Edgar ◽  
Peter R. Hoskins ◽  
...  
Keyword(s):  
Strong Association ◽  
Mouse Retina ◽  
Driving Mechanism ◽  
Vascular Networks ◽  
Vascular Remodelling ◽  
Zebrafish Model ◽  
Computational Framework ◽  
Heterogeneous Distribution ◽  
Sprouting Angiogenesis ◽  
Plasma Skimming

Sprouting angiogenesis is an essential vascularization mechanism consisting of sprouting and remodelling. The remodelling phase is driven by rearrangements of endothelial cells (ECs) within the post-sprouting vascular plexus. Prior work has uncovered how ECs polarize and migrate in response to flow-induced wall shear stress (WSS). However, the question of how the presence of erythrocytes (widely known as red blood cells (RBCs)) and their impact on haemodynamics affect vascular remodelling remains unanswered. Here, we devise a computational framework to model cellular blood flow in developmental mouse retina. We demonstrate a previously unreported highly heterogeneous distribution of RBCs in primitive vasculature. Furthermore, we report a strong association between vessel regression and RBC hypoperfusion, and identify plasma skimming as the driving mechanism. Live imaging in a developmental zebrafish model confirms this association. Taken together, our results indicate that RBC dynamics are fundamental to establishing the regional WSS differences driving vascular remodelling via their ability to modulate effective viscosity.

scholarly journals Association between erythrocyte dynamics and vessel remodelling in developmental vascular networks

2020 ◽  
Author(s):  
Qi Zhou ◽  
Tijana Perovic ◽  
Ines Fechner ◽  
Lowell T. Edgar ◽  
Peter R. Hoskins ◽  
...  
Keyword(s):  
Blood Flow ◽  
Shear Stress ◽  
Wall Shear Stress ◽  
Strong Association ◽  
Vascular Networks ◽  
Vascular Remodelling ◽  
Sprouting Angiogenesis ◽  
Vessel Regression ◽  
Wall Shear

AbstractSprouting angiogenesis is an essential vascularisation mechanism consisting of sprouting and remodelling. The remodelling phase is driven by rearrangements of endothelial cells (ECs) within the post-sprouting vascular plexus. Prior work has uncovered how ECs polarise and migrate in response to flow-induced wall shear stress (WSS). However, the question of how the presence of erythrocytes (well-known as RBCs) and their haemodynamics impact affects vascular remodelling remains unanswered. Here, we devise a computational framework to model cellular blood flow in developmental mouse retina. We demonstrate a previously unreported highly heterogeneous distribution of RBCs in primitive vasculature. Furthermore, we report a strong association between vessel regression and RBC depletion, and identify plasma skimming as the driving mechanism. Live imaging in a developmental zebrafish model confirms this association. Taken together, our results indicate that RBC dynamics are fundamental to establishing the regional WSS differences driving vascular remodelling via their ability to modulate effective viscosity.SummaryRecent studies demonstrate that during sprouting angiogenesis, blood flow provides crucial hydrodynamic cues (e.g. wall shear stress) for the remodelling of primitive plexuses towards a functional network. Notwithstanding, the role of RBCs in this process remains poorly understood. We report on the inherent heterogeneity of RBC perfusion within primitive vasculatures, and uncover a strong association between RBC depletion and vessel regression. Our work indicates the essential role of RBC dynamics in the establishment of regional WSS differences driving vascular remodelling. The RBC-driven process of pruning cell-depleted vessels not only importantly contributes to the optimal patterning of vascular networks during development, but also provides a remodelling mechanism to support clinical findings of microangiopathic complications associated with impaired RBC deformability in diseases such as diabetes mellitus and hypertension.

scholarly journals LIM Homeobox 4 (lhx4) regulates retinal neural differentiation and visual function in zebrafish

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rui Guo ◽  
Kangkang Ge ◽  
Yuying Wang ◽  
Minxia Lu ◽  
Fei Li ◽  
...  
Keyword(s):  
Visual Function ◽  
Neural Differentiation ◽  
Light Stimulus ◽  
Outer Nuclear Layer ◽  
Amacrine Cells ◽  
Bipolar Cells ◽  
Mouse Retina ◽  
Zebrafish Model ◽  
And Function

AbstractLIM homeobox 4 (LHX4) is expressed in the photoreceptors (PRs) of the outer nuclear layer (ONL) and bipolar cells (BCs) of the inner nuclear layer (INL) in mouse and chicken retina. It regulates the subtype-specific development of rod BCs and cone BCs in the mouse retina. However, no report has been published on its expression and function in the zebrafish retina. In this study, we assessed the expression of Lhx4 using in situ hybridization (ISH) technique and explored its role in zebrafish (Danio rerio) retinal development via morpholino (MO) technology. We found that the expression of lhx4 in the zebrafish retina begins 48 h post-fertilization (hpf) and is continuously expressed in the ONL and INL. A zebrafish model constructed with lhx4 knockdown in the eyes through vivo-MO revealed that: lhx4 knockdown inhibits the differentiation of Parvalbumin+ amacrine cells (ACs) and Rhodopsin+ rod photoreceptors (RPs), enhances the expression of visual system homeobox 2 (vsx2); and damages the responses of zebrafish to light stimulus, without affecting the differentiation of OFF-BCs and rod BCs, and apoptosis in the retina. These findings reveal that lhx4 regulates neural differentiation in the retina and visual function during zebrafish embryonic development.

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 Tumor Vessels Fuel the Fire in Glioblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6514
Author(s):  
Sara Rosińska ◽  
Julie Gavard
Keyword(s):  
Brain Tumors ◽  
Embryonic Development ◽  
Blood Vessel ◽  
Tumor Cells ◽  
Cancer Therapies ◽  
Vascular Networks ◽  
Tumor Mass ◽  
Sprouting Angiogenesis ◽  
Anti Cancer ◽  
Vascular Mimicry

Glioblastoma, a subset of aggressive brain tumors, deploy several means to increase blood vessel supply dedicated to the tumor mass. This includes typical program borrowed from embryonic development, such as vasculogenesis and sprouting angiogenesis, as well as unconventional processes, including co-option, vascular mimicry, and transdifferentiation, in which tumor cells are pro-actively engaged. However, these neo-generated vascular networks are morphologically and functionally abnormal, suggesting that the vascularization processes are rather inefficient in the tumor ecosystem. In this review, we reiterate the specificities of each neovascularization modality in glioblastoma, and, how they can be hampered mechanistically in the perspective of anti-cancer therapies.

scholarly journals A computational diffusion model to study antibody transport within reconstructed tumor microenvironments

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ana Luísa Cartaxo ◽  
Jaime Almeida ◽  
Emilio J. Gualda ◽  
Maria Marsal ◽  
Pablo Loza-Alvarez ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Fluorescent Antibody ◽  
Light Sheet ◽  
In Vitro Models ◽  
Experimental Models ◽  
Computational Framework ◽  
Heterogeneous Distribution ◽  
Alginate Capsules

Abstract Background Antibodies revolutionized cancer treatment over the past decades. Despite their successfully application, there are still challenges to overcome to improve efficacy, such as the heterogeneous distribution of antibodies within tumors. Tumor microenvironment features, such as the distribution of tumor and other cell types and the composition of the extracellular matrix may work together to hinder antibodies from reaching the target tumor cells. To understand these interactions, we propose a framework combining in vitro and in silico models. We took advantage of in vitro cancer models previously developed by our group, consisting of tumor cells and fibroblasts co-cultured in 3D within alginate capsules, for reconstruction of tumor microenvironment features. Results In this work, an experimental-computational framework of antibody transport within alginate capsules was established, assuming a purely diffusive transport, combined with an exponential saturation effect that mimics the saturation of binding sites on the cell surface. Our tumor microenvironment in vitro models were challenged with a fluorescent antibody and its transport recorded using light sheet fluorescence microscopy. Diffusion and saturation parameters of the computational model were adjusted to reproduce the experimental antibody distribution, with root mean square error under 5%. This computational framework is flexible and can simulate different random distributions of tumor microenvironment elements (fibroblasts, cancer cells and collagen fibers) within the capsule. The random distribution algorithm can be tuned to follow the general patterns observed in the experimental models. Conclusions We present a computational and microscopy framework to track and simulate antibody transport within the tumor microenvironment that complements the previously established in vitro models platform. This framework paves the way to the development of a valuable tool to study the influence of different components of the tumor microenvironment on antibody transport.

scholarly journals Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression

2018 ◽  
Vol 217 (5) ◽  
pp. 1651-1665 ◽  
Author(s):  
Anne-Clémence Vion ◽  
Silvanus Alt ◽  
Alexandra Klaus-Bergmann ◽  
Anna Szymborska ◽  
Tuyu Zheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Shear Stress ◽  
Cell Cycle Progression ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Low Flow ◽  
Mouse Retina ◽  
Vascular Networks ◽  
Enhanced Sensitivity

Blood flow shapes vascular networks by orchestrating endothelial cell behavior and function. How endothelial cells read and interpret flow-derived signals is poorly understood. Here, we show that endothelial cells in the developing mouse retina form and use luminal primary cilia to stabilize vessel connections selectively in parts of the remodeling vascular plexus experiencing low and intermediate shear stress. Inducible genetic deletion of the essential cilia component intraflagellar transport protein 88 (IFT88) in endothelial cells caused premature and random vessel regression without affecting proliferation, cell cycle progression, or apoptosis. IFT88 mutant cells lacking primary cilia displayed reduced polarization against blood flow, selectively at low and intermediate flow levels, and have a stronger migratory behavior. Molecularly, we identify that primary cilia endow endothelial cells with strongly enhanced sensitivity to bone morphogenic protein 9 (BMP9), selectively under low flow. We propose that BMP9 signaling cooperates with the primary cilia at low flow to keep immature vessels open before high shear stress–mediated remodeling.

scholarly journals PRL-2 phosphatase is required for vascular morphogenesis and angiogenic signaling

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Mathilde Poulet ◽  
Jacinthe Sirois ◽  
Kevin Boyé ◽  
Noriko Uetani ◽  
Serge Hardy ◽  
...  
Keyword(s):  
Cell Culture ◽  
Biological Function ◽  
Protein Tyrosine Phosphatases ◽  
Endothelial Cell Migration ◽  
Mouse Retina ◽  
Notch 1 ◽  
Sprouting Angiogenesis ◽  
Vascular Morphogenesis ◽  
Novel Therapeutic ◽  
Prl Phosphatases

Abstract Protein tyrosine phosphatases are essential modulators of angiogenesis and have been identified as novel therapeutic targets in cancer and anti-angiogenesis. The roles of atypical Phosphatase of Regenerative Liver (PRL) phosphatases in this context remain poorly understood. Here, we investigate the biological function of PRL phosphatases in developmental angiogenesis in the postnatal mouse retina and in cell culture. We show that endothelial cells in the retina express PRL-2 encoded by the Ptp4a2 gene, and that inducible endothelial and global Ptp4a2 mutant mice exhibit defective retinal vascular outgrowth, arteriovenous differentiation, and sprouting angiogenesis. Mechanistically, PTP4A2 deletion limits angiogenesis by inhibiting endothelial cell migration and the VEGF-A, DLL-4/NOTCH-1 signaling pathway. This study reveals the importance of PRL-2 as a modulator of vascular development.

scholarly journals Non-canonical Wnt signaling regulates junctional mechanocoupling during angiogenic collective cell migration

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Joana R Carvalho ◽  
Isabela C Fortunato ◽  
Catarina G Fonseca ◽  
Anna Pezzarossa ◽  
Pedro Barbacena ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Wnt Signaling ◽  
Fine Tuning ◽  
Cell Behavior ◽  
Collective Cell Migration ◽  
Vascular Networks ◽  
Canonical Wnt Signaling ◽  
Sprouting Angiogenesis ◽  
Canonical Wnt

Morphogenesis of hierarchical vascular networks depends on the integration of multiple biomechanical signals by endothelial cells, the cells lining the interior of blood vessels. Expansion of vascular networks arises through sprouting angiogenesis, a process involving extensive cell rearrangements and collective cell migration. Yet, the mechanisms controlling angiogenic collective behavior remain poorly understood. Here, we show this collective cell behavior is regulated by non-canonical Wnt signaling. We identify that Wnt5a specifically activates Cdc42 at cell junctions downstream of ROR2 to reinforce coupling between adherens junctions and the actin cytoskeleton. We show that Wnt5a signaling stabilizes vinculin binding to alpha-catenin, and abrogation of vinculin in vivo and in vitro leads to uncoordinated polarity and deficient sprouting angiogenesis in Mus musculus. Our findings highlight how non-canonical Wnt signaling coordinates collective cell behavior during vascular morphogenesis by fine-tuning junctional mechanocoupling between endothelial cells.

scholarly journals Blood flow coordinates collective endothelial cell migration during vascular plexus formation and promotes angiogenic sprout regression via vegfr3/flt4

2021 ◽  
Author(s):  
Yan Chen ◽  
Zhen Jiang ◽  
Katherine H Fisher ◽  
Hyejeong Rosemary Kim ◽  
Paul C Evans ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Blood Vessels ◽  
Endothelial Cell Migration ◽  
Vascular Networks ◽  
Vascular Remodelling ◽  
Venous Plexus ◽  
Vascular Plexus ◽  
And Migration

Nascent vascular networks adapt to the increasing metabolic demands of growing tissues by expanding via angiogenesis. As vascular networks expand, blood vessels remodel, progressively refining vascular connectivity to generate a more haemodynamically efficient network. This process is driven by interplay between endothelial cell (EC) signalling and blood flow. While much is known about angiogenesis, considerably less is understood of the mechanisms underlying vessel remodelling by blood flow. Here we employ the zebrafish sub-intestinal venous plexus (SIVP) to characterise the mechanisms underlying blood flow-dependent remodelling. Using live imaging to track ECs we show that blood flow controls SIVP remodelling by coordinating collective migration of ECs within the developing plexus. Blood flow opposes continuous ventral EC migration within the SIVP and is required for regression of angiogenic sprouts to support plexus growth. Sprout regression occurs by coordinated polarisation and migration of ECs from non-perfused leading sprouts, which migrate in opposition to blood flow and incorporate into the SIV. Sprout regression is compatible with low blood flow and is dependent upon vegfr3/flt4 function under these conditions. Blood flow limits expansive venous remodelling promoted by vegfr3/flt4. Collectively, these studies reveal how blood flow sculpts a developing vascular plexus by coordinating EC migration and balancing vascular remodelling via vegfr3/flt4

scholarly journals YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Filipa Neto ◽  
Alexandra Klaus-Bergmann ◽  
Yu Ting Ong ◽  
Silvanus Alt ◽  
Anne-Clémence Vion ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Adherens Junction ◽  
Tissue Growth ◽  
Bmp Signaling ◽  
Vascular Networks ◽  
Sprouting Angiogenesis ◽  
Local Aggregation ◽  
Bmp Signalling ◽  
Vessel Networks

Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels.

Sign in / Sign up

Export Citation Format

Share Document