Integration of vascular progenitors into functional blood vessels represents a novel mechanism of vascular growth

During embryogenesis, the initial vascular network is thought to form by the process of vasculogenesis, or the specification of vascular progenitors de novo. After the initial blood circulation has been established, the majority of later-forming vessels are thought to arise by angiogenesis from the already established vasculature. Here we show that new vascular progenitors in zebrafish embryos contribute to functional vasculature even after blood circulation has been established. Based on the expression analysis of early vascular progenitor markers etv2 and tal1, we characterized a novel site of late vasculogenesis (termed secondary vascular field, SVF), located bilaterally along the yolk extension. Using time-lapse imaging of etv2 reporter lines, we show that SVF cells migrate and incorporate into functional blood vessels and contribute to the formation of the posterior cardinal vein and subintestinal vasculature, suggesting a novel mode of vascular growth. We further demonstrate that SVF cells participate in vascular recovery after chemical ablation of vascular endothelial cells. Inducible inhibition of etv2 function prevented SVF cell differentiation and resulted in the defective formation of subintestinal vasculature. In addition, we performed single-cell RNA-seq analysis to identify the transcriptional profile of SVF cells, which demonstrated similarities and differences between the transcriptomes of SVF cells and early vascular progenitors. Our results characterize a novel mechanism of how new vascular progenitors incorporate into established vasculature and revise our understanding of basic mechanisms that regulate vascular development.

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Single-cell RNA-seq reveals lineage-specific regulatory changes of fibroblasts and vascular endothelial cells in keloids

Journal of Investigative Dermatology ◽

10.1016/j.jid.2021.06.010 ◽

2021 ◽

Author(s):

Xuanyu Liu ◽

Wen Chen ◽

Qingyi Zeng ◽

Baihui Ma ◽

Zhujun Li ◽

...

Keyword(s):

Endothelial Cells ◽

Single Cell ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Rna Seq ◽

Regulatory Changes

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TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms23010448 ◽

2021 ◽

Vol 23 (1) ◽

pp. 448

Author(s):

Keisuke Ito ◽

Tomoya Fujie ◽

Masahiro Shimomura ◽

Tsuyoshi Nakano ◽

Chika Yamamoto ◽

...

Keyword(s):

Endothelial Cells ◽

Blood Vessels ◽

Transforming Growth Factor ◽

Vascular Endothelial Cells ◽

Extracellular Fluid ◽

Mitogen Activated Protein Kinase ◽

Signal Pathways ◽

Vascular Endothelial ◽

Metal Transporter ◽

Tgf Β1

Vascular endothelial cells cover the luminal surface of blood vessels in a monolayer and play a role in the regulation of vascular functions, such as the blood coagulation-fibrinolytic system. When the monolayer is severely or repeatedly injured, platelets aggregate at the damaged site and release transforming growth factor (TGF)-β1 in large quantities from their α-granules. Cadmium is a heavy metal that is toxic to various organs, including the kidneys, bones, liver, and blood vessels. Our previous study showed that the expression level of Zrt/Irt-related protein 8 (ZIP8), a metal transporter that transports cadmium from the extracellular fluid into the cytosol, is a crucial factor in determining the sensitivity of vascular endothelial cells to cadmium cytotoxicity. In the present study, TGF-β1 was discovered to potentiate cadmium-induced cytotoxicity by increasing the intracellular accumulation of cadmium in cells. Additionally, TGF-β1 induced the expression of ZIP8 via the activin receptor-like kinase 5-Smad2/3 signaling pathways; Smad3-mediated induction of ZIP8 was associated with or without p38 mitogen-activated protein kinase (MAPK). These results suggest that the cytotoxicity of cadmium to vascular endothelial cells increases when damaged endothelial monolayers that are highly exposed to TGF-β1 are repaired.

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Antifungal benzimidazoles disrupt vasculature by targeting one of nine β-tubulins

10.1101/2020.09.15.298828 ◽

2020 ◽

Author(s):

Riddhiman K. Garge ◽

Hye Ji Cha ◽

Chanjae Lee ◽

Jimmy D. Gollihar ◽

Aashiq H. Kachroo ◽

...

Keyword(s):

Blood Vessels ◽

Vascular Endothelial Cells ◽

Tissue Level ◽

Clinical Applications ◽

Vascular Endothelial ◽

Human Cell Culture ◽

Vascular Disrupting Agent ◽

Tubulin Isotypes ◽

Vascular Disruption ◽

Resistance Data

ABSTRACTThiabendazole (TBZ) is an FDA-approved benzimidazole widely used for its antifungal and antihelminthic properties. We showed previously that TBZ is also a potent vascular disrupting agent and inhibits angiogenesis at the tissue level by dissociating vascular endothelial cells in newly formed blood vessels. Here, we uncover TBZ’s molecular target and mechanism of action. Using human cell culture, molecular modeling, and humanized yeast, we find that TBZ selectively targets only 1 of 9 human β-tubulin isotypes (TUBB8) to specifically disrupt endothelial cell microtubules. By leveraging epidemiological pesticide resistance data and mining chemical features of commercially used benzimidazoles, we discover that a broader class of benzimidazole compounds, in extensive use for 50 years, also potently disrupt immature blood vessels and inhibit angiogenesis. Thus, besides identifying the molecular mechanism of benzimidazole-mediated vascular disruption, this study presents evidence relevant to the widespread use of these compounds while offering potential new clinical applications.

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Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors

Journal of Clinical Medicine ◽

10.3390/jcm8111980 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1980 ◽

Cited By ~ 2

Author(s):

Bin Ren ◽

J. Bart Rose ◽

Yehe Liu ◽

Renata Jaskular-Sztul ◽

Carlo Contreras ◽

...

Keyword(s):

Endothelial Cells ◽

Neuroendocrine Tumors ◽

De Novo ◽

Vascular Endothelial Cells ◽

Antiangiogenic Therapy ◽

Notch Pathway ◽

Vascular Endothelial ◽

Pancreatic Neuroendocrine Tumors ◽

Bioactive Substances ◽

Therapeutic Implications

Arteriogenesis supplies oxygen and nutrients in the tumor microenvironment (TME), which may play an important role in tumor growth and metastasis. Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic malignancy and are frequently metastatic on presentation. Nearly a third of pNETs secrete bioactive substances causing debilitating symptoms. Current treatment options for metastatic pNETs are limited. Importantly, these tumors are highly vascularized and heterogeneous neoplasms, in which the heterogeneity of vascular endothelial cells (ECs) and de novo arteriogenesis may be critical for their progression. Current anti-angiogenetic targeted treatments have not shown substantial clinical benefits, and they are poorly tolerated. This review article describes EC heterogeneity and heterogeneous tumor-associated ECs (TAECs) in the TME and emphasizes the concept of de novo arteriogenesis in the TME. The authors also emphasize the challenges of current antiangiogenic therapy in pNETs and discuss the potential of tumor arteriogenesis as a novel therapeutic target. Finally, the authors prospect the clinical potential of targeting the FoxO1-CD36-Notch pathway that is associated with both pNET progression and arteriogenesis and provide insights into the clinical implications of targeting plasticity of cancer stem cells (CSCs) and vascular niche, particularly the arteriolar niche within the TME in pNETs, which will also provide insights into other types of cancer, including breast cancer, lung cancer, and malignant melanoma.

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Extracellular ATP signaling and P2X nucleotide receptors in monolayers of primary human vascular endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.01387.2000 ◽

2002 ◽

Vol 282 (2) ◽

pp. C289-C301 ◽

Cited By ~ 96

Author(s):

Lisa M. Schwiebert ◽

William C. Rice ◽

Brian A. Kudlow ◽

Amanda L. Taylor ◽

Erik M. Schwiebert

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Blood Vessels ◽

Vascular Tone ◽

Vascular Endothelial Cells ◽

Purinergic Signaling ◽

Primary Cultures ◽

Atp Release ◽

Vascular Endothelial ◽

Multiple Blood

ATP and its metabolites regulate vascular tone; however, the sources of the ATP released in vascular beds are ill defined. As such, we tested the hypothesis that all limbs of an extracellular purinergic signaling system are present in vascular endothelial cells: ATP release, ATP receptors, and ATP receptor-triggered signal transduction. Primary cultures of human endothelial cells derived from multiple blood vessels were grown as monolayers and studied using a bioluminescence detection assay for ATP released into the medium. ATP is released constitutively and exclusively across the apical membrane under basal conditions. Hypotonic challenge or the calcium agonists ionomycin and thapsigargin stimulate ATP release in a reversible and regulated manner. To assess expression of P2X purinergic receptor channel subtypes (P2XRs), we performed degenerate RT-PCR, sequencing of the degenerate P2XR product, and immunoblotting with P2XR subtype-specific antibodies. Results revealed that P2X4and P2X5are expressed abundantly by endothelial cell primary cultures derived from multiple blood vessels. Together, these results suggest that components of an autocrine purinergic signaling loop exist in the endothelial cell microvasculature that may allow for “self-regulation” of endothelial cell function and modulation of vascular tone.

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Statin-induced apoptosis of vascular endothelial cells is blocked by dexamethasone

Journal of Endocrinology ◽

10.1677/joe.0.1740007 ◽

2002 ◽

Vol 174 (1) ◽

pp. 7-16 ◽

Cited By ~ 37

Author(s):

CJ Newton ◽

G Ran ◽

YX Xie ◽

D Bilko ◽

CH Burgoyne ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cell Survival ◽

Cell Line ◽

De Novo ◽

Vascular Endothelial Cells ◽

Pcr Analysis ◽

Vascular Endothelial ◽

Endothelial Cell Line ◽

Induced Apoptosis

Statins block de novo synthesis of cholesterol by inhibiting the enzyme, HMG CoA reductase. The product of this reaction, mevalonic acid, is also a precursor of isoprenoids, molecules required for the activation of signalling G-proteins, such as Ras. Signal transduction pathways involving Ras are important for cell survival and this may be why statins induce apoptotic death of several cell types. Given that statins are used to treat vascular disease, it is surprising that no studies have been conducted on vascular endothelial cells. For this reason, we have tested the effect of fluvastatin (FS) on the endothelial cell line EA.hy 926. Here we show that FS, at concentrations from 1 to 2 microM, blocks growth and induces apoptosis of the endothelial cell line, EA.hy 926. As considerable redundancy exists in cell signalling pathways for cell survival, toxicity of FS under more physiological conditions might be prevented by pathways that do not require Ras, such as those activated by adrenal or sex steroids. To test this hypothesis, first RT-PCR analysis was performed for nuclear receptor mRNA expression. This revealed the presence of mRNA for the androgen receptor (AR) and glucocorticoid receptor (GR). The effect of the AR agonist, dihydrotestosterone (DHT), and the GR agonist, dexamethasone (Dex), was then tested. Whilst DHT (100 nM) had no effect on FS-induced cell death, Dex (1 microM) blocked FS-induced apoptosis. Cell cycle analysis revealed that 24 h exposure to FS prevented cells from leaving G(1) and 24-48 h later a marked sub-G(1) peak was observed. Dex was able to reduce the sub-G(1) peak, but it failed to reduce accumulation of cells in G(1). Further studies revealed that, in addition to blocking FS-induced apoptosis, Dex was able to block apoptosis of EA.hy 926 cells induced by serum deprivation, tumour necrosis factor-alpha, oxidants, DNA damage and mitochondrial disruption. This study strongly suggests that glucocorticoids have a role to play in preventing vascular injury and they may provide a reason why statins are apparently not toxic to vascular endothelial cells in vivo.

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Anti-VEGF Therapy in Breast and Lung Mouse Models of Cancers

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/947928 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

Di Domenico Marina ◽

Ricciardi Carmela ◽

Fusco Alfredo ◽

Pierantoni Giovanna Maria

Keyword(s):

Vascular Endothelial Growth Factor ◽

Targeted Therapy ◽

Blood Vessels ◽

Blood Circulation ◽

The Body ◽

Vascular Endothelial ◽

Murine Models ◽

Body Tissues ◽

The World ◽

Endothelial Growth Factor

Cancer is the second leading cause of death in the world after cardiovascular diseases. Some types of cancer cells often travel to other parts of the body through blood circulation or lymph vessels, where they begin to grow. This process is recognized as metastasis. Angiogenesis is the formation of new blood vessels from existing vessel. Normally angiogenesis is a healthy process, that helps the body to heal wounds and repair damaged body tissues, whereas in cancerous condition this process supports new blood vessels formation that provide a tumor with its own blood supply, nutrients and allow it to grow. The most important proximal factor for angiogenesis is the vascular endothelial growth factor VEGF. Angioinhibition is a form of targeted therapy that uses drugs to stop tumors from making new blood vessels. Therefore, in this paper we analyse the importance of VEGF as target of cancer therapy, analysing murine models.

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Surface-retained tPA is essential for effective fibrinolysis on vascular endothelial cells

Blood ◽

10.1182/blood-2011-05-353912 ◽

2011 ◽

Vol 118 (11) ◽

pp. 3182-3185 ◽

Cited By ~ 25

Author(s):

Yuko Suzuki ◽

Hideki Yasui ◽

Tomasz Brzoska ◽

Hideo Mogami ◽

Tetsumei Urano

Keyword(s):

Endothelial Cells ◽

Cell Surface ◽

Enzymatic Activity ◽

De Novo ◽

Vascular Endothelial Cells ◽

Secretory Granules ◽

Vascular Endothelial Cell ◽

Clot Lysis ◽

Dependent Manner ◽

Vascular Endothelial

Abstract In a previous study, we demonstrated unique secretory dynamics of tissue plasminogen activator (tPA) in which tPA was retained on the cell surface in a heavy chain–dependent manner after exocytosis from secretory granules in vascular endothelial cells. Here, we examined how retained tPA expresses its enzymatic activity. Retained tPA effectively increased the lysine binding site–dependent binding of plasminogen on the cell surface and pericellular area; this was abolished by inhibition of enzymatic activity of either tPA or plasmin, which suggests that de novo generation of carboxyl-terminal lysine as a consequence of degradation of surface/pericellular proteins by plasmin is essential. Retained tPA initiated zonal clot lysis of a fibrin network that had been formed on vascular endothelial cells, which was preceded by the binding of plasminogen to the lysis front. Our results provide evidence that secreted and retained tPA is essential for maintaining both high fibrinolytic activity and effective clot lysis on the vascular endothelial cell surface.

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