Tetramethylpyrazine Ameliorates Peritoneal Angiogenesis by Regulating VEGF/Hippo/YAP Signaling

Angiogenesis of human peritoneal vascular endothelial cells (HPVECs), linked to vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling, is a complication of peritoneal fibrosis (PF). Hippo/YAP signaling interacts with VEGF/VEGFR2 signaling, but the effect on peritoneal angiogenesis and PF has not been studied. We tested VEGF/Hippo/YAP inhibition by tetramethylpyrazine (TMP) in PF mice and HPVECs. This treatment ameliorated peritoneal dialysis (PD)–induced angiogenesis and PF. In mice, PF was associated with upregulation of VEGF, and TMP ameliorated submesothelial fibrosis, perivascular bleeding, and Collagen I abundance. In HPVECs, angiogenesis occurred due to human peritoneal mesothelial cells (HPMCs)–conditioned medium, and TMP alleviated HPVECs migration, tube formation, and YAP nuclear translocation. YAP knockdown PF mouse and HPVEC models were established to further confirm our finding. YAP deletion attenuated the PD-induced or VEGF-induced increase in angiogenesis and PF. The amount of CYR61 and CTGF was significantly less in the YAP knockdown group. To study the possibility that TMP could benefit angiogenesis, we measured the HPVECs migration and tube formation and found that both were sharply increased in YAP overexpression; TMP treatment partly abolished these increases. As well, the amount of VEGFR localized in the trans-Golgi network was lower by double immunofluorescence; VEGFR and its downstream signaling pathways including p-ERK, p-P38, and p-Akt were more in HPVECs with YAP overexpression. Overall, TMP treatment ameliorated angiogenesis, PF, and peritoneum injury. These changes were accompanied by inhibition of VEGF/Hippo/YAP.

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Islet vascularization is regulated by primary endothelial cilia via VEGF-A-dependent signaling

eLife ◽

10.7554/elife.56914 ◽

2020 ◽

Vol 9 ◽

Author(s):

Yan Xiong ◽

M Julia Scerbo ◽

Anett Seelig ◽

Francesco Volta ◽

Nils O'Brien ◽

...

Keyword(s):

Endothelial Cells ◽

Primary Cilia ◽

Capillary Density ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Downstream Signaling ◽

Vegfr2 Signaling ◽

And Migration ◽

Endothelial Growth Factor

Islet vascularization is essential for intact islet function and glucose homeostasis. We have previously shown that primary cilia directly regulate insulin secretion. However, it remains unclear whether they are also implicated in islet vascularization. At eight weeks, murine Bbs4-/-islets show significantly lower intra-islet capillary density with enlarged diameters. Transplanted Bbs4-/- islets exhibit delayed re-vascularization and reduced vascular fenestration after engraftment, partially impairing vascular permeability and glucose delivery to β-cells. We identified primary cilia on endothelial cells as the underlying cause of this regulation, via the vascular endothelial growth factor-A (VEGF-A)/VEGF receptor 2 (VEGFR2) pathway. In vitro silencing of ciliary genes in endothelial cells disrupts VEGF-A/VEGFR2 internalization and downstream signaling. Consequently, key features of angiogenesis including proliferation and migration are attenuated in human BBS4 silenced endothelial cells. We conclude that endothelial cell primary cilia regulate islet vascularization and vascular barrier function via the VEGF-A/VEGFR2 signaling pathway.

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Tim-3 promotes tube formation and decreases tight junction formation in vascular endothelial cells

Bioscience Reports ◽

10.1042/bsr20202130 ◽

2020 ◽

Vol 40 (10) ◽

Author(s):

Yizi Cong ◽

Xingmiao Wang ◽

Suxia Wang ◽

Guangdong Qiao ◽

Yalun Li ◽

...

Keyword(s):

Endothelial Cells ◽

Tight Junction ◽

Immune Escape ◽

Vascular Endothelial Cells ◽

Tumour Progression ◽

Umbilical Vein ◽

Tube Formation ◽

In Vitro Assays ◽

Vegf Receptor ◽

Vascular Endothelial

Abstract As a negative immune checkpoint molecule, T-cell immunoglobulin domain and mucin domain containing molecule-3 (Tim-3) has been found to serve a crucial role in immune escape and tumour progression. Previous studies have reported that Tim-3 is important to endothelial cells and it has also been demonstrated to be involved in numerous types of human diseases, including melanoma, lymphoma, rickettsial infection and atherosclerosis; however, its exact mechanism of action remains largely unknown. In the present study, Tim-3 was overexpressed in vascular endothelial human lung microvascular endothelial cells (HMVECs) and human umbilical vein endothelial cells (HUVECs), and in vitro assays were used to determine that Tim-3 promoted cell proliferation, migration, invasion and tube formation through activating cyclin D1 (CCND1), Ras homolog gene family member A and vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2). Additionally, Tim-3 decreased tight junction (TJ) formation and the transepithelial resistance (TER) of endothelial cells by decreasing the expression levels of TJ protein 2, Occludin and claudin 1 (CLND1). In conclusion, these findings suggested that Tim-3 may exert a positive role in angiogenesis and a negative role in TJ formation in vascular endothelial cells, which may provide novel strategies for the treatment of Tim-3-associated diseases.

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Spatial and temporal VEGF receptor intracellular trafficking in microvascular and macrovascular endothelial cells

Scientific Reports ◽

10.1038/s41598-021-96964-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Juliete A. F. Silva ◽

Xiaoping Qi ◽

Maria B. Grant ◽

Michael E. Boulton

Keyword(s):

Endothelial Cells ◽

Nuclear Translocation ◽

Vascular Endothelial Cells ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Intracellular Organelles ◽

Endosomal Pathway ◽

Endothelial Growth Factor

AbstractThe vascular endothelial growth factor receptors (VEGFRs) can shape the neovascular phenotype of vascular endothelial cells when translocated to the nucleus, however the spatial and temporal changes in the intracellular distribution and translocation of VEGFRs to the nucleus and the organelles involved in this process is unclear. This study reports the effect of exogenous VEGF on translocation of VEGFRs and organelles in micro- and macrovascular endothelial cells. We showed that VEGF is responsible for: a rapid and substantial nuclear translocation of VEGFRs; VEGFR1 and VEGFR2 exhibit distinct spatial, temporal and structural translocation characteristics both in vitro and in vivo and this determines the nuclear VEGFR1:VEGFR2 ratio which differs between microvascular and macrovascular cells; VEGFR2 nuclear translocation is associated with the endosomal pathway transporting the receptor from Golgi in microvascular endothelial cells; and an increase in the volume of intracellular organelles. In conclusion, the nuclear translocation of VEGFRs is both receptor and vessel (macro versus micro) dependent and the endosomal pathway plays a key role in the translocation of VEGFRs to the nucleus and the subsequent export to the lysosomal system. Modulating VEGF-mediated VEGFR1 and VEGFR2 intracellular transmigration pathways may offer an alternative for the development of new anti-angiogenic therapies.

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Occlusal hypofunction causes periodontal atrophy and VEGF/VEGFR inhibition in tooth movement

The Angle Orthodontist ◽

10.2319/011712-45.1 ◽

2012 ◽

Vol 83 (1) ◽

pp. 48-56 ◽

Cited By ~ 14

Author(s):

Risa Usumi-Fujita ◽

Jun Hosomichi ◽

Noriaki Ono ◽

Naoki Shibutani ◽

Sawa Kaneko ◽

...

Keyword(s):

Tooth Movement ◽

Vascular Endothelial Cells ◽

Compressive Force ◽

Terminal Deoxynucleotidyl Transferase ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Sprague Dawley ◽

Micro Computed Tomography ◽

Normal Occlusion ◽

Titanium Nickel

Abstract Objective: To examine changes in microvasculature and the expression of vascular endothelial growth factor A (VEGF-A) and VEGF receptor 2 (VEGFR-2) in rat hypofunctional periodontal ligament (PDL) during experimental tooth movement. Materials and Methods: Twelve-week-old male Sprague-Dawley rats were divided into normal occlusion and occlusal hypofunction groups. After a 2-week bite-raising period, rat first molar was moved mesially using a 10-gf titanium-nickel alloy closed coil spring in both groups. On days 0, 1, 2, 3, and 7 after tooth movement, histologic changes were examined by micro–computed tomography and immunohistochemistry using CD31, VEGF-A, VEGFR-2, and the terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method. Results: Hypofunctional molars inclined more than normal molars and did not move notably after day 1 of tooth movement. Blood vessels increased on the tension side of the PDL in normal teeth. Immunoreactivities for VEGF-A and VEGFR-2 in normal teeth were greater than those in hypofunctional teeth during tooth movement. Compressive force rapidly caused apoptosis of the PDL and vascular endothelial cells in hypofunctional teeth, but not in normal teeth. Conclusions: Occlusal hypofunction induces vascular constriction through a decrease in the expression of VEGF-A and VEGFR-2, and apoptosis of the PDL and vascular cells occurs during tooth movement.

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Peroxiredoxin II Is an Essential Antioxidant Enzyme that Prevents the Oxidative Inactivation of VEGF Receptor-2 in Vascular Endothelial Cells

Molecular Cell ◽

10.1016/j.molcel.2011.08.040 ◽

2011 ◽

Vol 44 (4) ◽

pp. 545-558 ◽

Cited By ~ 85

Author(s):

Dong Hoon Kang ◽

Doo Jae Lee ◽

Kyung Wha Lee ◽

Yoon Sun Park ◽

Joo Young Lee ◽

...

Keyword(s):

Endothelial Cells ◽

Antioxidant Enzyme ◽

Vascular Endothelial Cells ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Oxidative Inactivation

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Tricyclic antidepressant amitriptyline inhibits autophagic flux and prevents tube formation in vascular endothelial cells

Basic & Clinical Pharmacology & Toxicology ◽

10.1111/bcpt.13146 ◽

2018 ◽

Vol 124 (4) ◽

pp. 370-384 ◽

Cited By ~ 5

Author(s):

Yinglu Guan ◽

Xiang Li ◽

Michihisa Umetani ◽

Krishna M. Boini ◽

Pin‐Lan Li ◽

...

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Tube Formation ◽

Tricyclic Antidepressant ◽

Autophagic Flux ◽

Vascular Endothelial

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CYLD regulates angiogenesis by mediating vascular endothelial cell migration

Blood ◽

10.1182/blood-2009-10-248526 ◽

2010 ◽

Vol 115 (20) ◽

pp. 4130-4137 ◽

Cited By ~ 52

Author(s):

Jinmin Gao ◽

Lei Sun ◽

Lihong Huo ◽

Min Liu ◽

Dengwen Li ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Migration ◽

Endothelial Cell ◽

Vascular Endothelial Cells ◽

Vascular Endothelial Cell ◽

Tube Formation ◽

Endothelial Cell Migration ◽

Vascular Endothelial

Cylindromatosis (CYLD) is a deubiquitinase that was initially identified as a tumor suppressor and has recently been implicated in diverse normal physiologic processes. In this study, we have investigated the involvement of CYLD in angiogenesis, the formation of new blood vessels from preexisting ones. We find that knockdown of CYLD expression significantly impairs angiogenesis in vitro in both matrigel-based tube formation assay and collagen-based 3-dimensional capillary sprouting assay. Disruption of CYLD also remarkably inhibits angiogenic response in vivo, as evidenced by diminished blood vessel growth into the angioreactors implanted in mice. Mechanistic studies show that CYLD regulates angiogenesis by mediating the spreading and migration of vascular endothelial cells. Silencing of CYLD dramatically decreases microtubule dynamics in endothelial cells and inhibits endothelial cell migration by blocking the polarization process. Furthermore, we identify Rac1 activation as an important factor contributing to the action of CYLD in regulating endothelial cell migration and angiogenesis. Our findings thus uncover a previously unrecognized role for CYLD in the angiogenic process and provide a novel mechanism for Rac1 activation during endothelial cell migration and angiogenesis.

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Viral Vascular Endothelial Growth Factor Plays a Critical Role in Orf Virus Infection

Journal of Virology ◽

10.1128/jvi.74.22.10699-10706.2000 ◽

2000 ◽

Vol 74 (22) ◽

pp. 10699-10706 ◽

Cited By ~ 95

Author(s):

Loreen J. Savory ◽

Steven A. Stacker ◽

Stephen B. Fleming ◽

Brian E. Niven ◽

Andrew A. Mercer

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Virus Infection ◽

Vascular Endothelial Cells ◽

Critical Role ◽

Skin Lesions ◽

Orf Virus ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Endothelial Growth Factor

ABSTRACT Infection by the parapoxvirus orf virus causes proliferative skin lesions in which extensive capillary proliferation and dilation are prominent histological features. This infective phenotype may be linked to a unique virus-encoded factor, a distinctive new member of the vascular endothelial growth factor (VEGF) family of molecules. We constructed a recombinant orf virus in which the VEGF-like gene was disrupted and show that inactivation of this gene resulted in the loss of three VEGF activities expressed by the parent virus: mitogenesis of vascular endothelial cells, induction of vascular permeability, and activation of VEGF receptor 2. We used the recombinant orf virus to assess the contribution of the viral VEGF to the vascular response seen during orf virus infection of skin. Our results demonstrate that the viral VEGF, while recognizing a unique profile of the known VEGF receptors (receptor 2 and neuropilin 1), is able to stimulate a striking proliferation of blood vessels in the dermis underlying the site of infection. Furthermore, the data demonstrate that the viral VEGF participates in promoting a distinctive pattern of epidermal proliferation. Loss of a functional viral VEGF resulted in lesions with markedly reduced clinical indications of infection. However, viral replication in the early stages of infection was not impaired, and only at later times did it appear that replication of the recombinant virus might be reduced.

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Vialinin A, an Edible Mushroom-Derived p-Terphenyl Antioxidant, Prevents VEGF-Induced Neovascularization In Vitro and In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/1052102 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Himangshu Sonowal ◽

Kirtikar Shukla ◽

Sumedha Kota ◽

Ashish Saxena ◽

Kota V. Ramana

Keyword(s):

Nuclear Translocation ◽

Vascular Endothelial Cell ◽

Natural Antioxidants ◽

Edible Mushroom ◽

Tube Formation ◽

Dependent Manner ◽

Vascular Endothelial ◽

In Vivo Models

Increased side toxicities and development of drug resistance are the major concern for the cancer chemotherapy using synthetic drugs. Therefore, identification of novel natural antioxidants with potential therapeutic efficacies is important. In the present study, we have examined how the antioxidant and anti-inflammatory activities of vialinin A, a p-terphenyl compound derived from Chinese edible mushroomT. terrestrisandT. vialis, prevents human umbilical vascular endothelial cell (HUVEC) neovascularization in vitro and in vivo models. Pretreatment of HUVECs with vialinin A prevents vascular endothelial growth factor- (VEGF) induced HUVEC cell growth in a dose-dependent manner. Further, vialinin A also inhibits VEGF-induced migration as well as tube formation of HUVECs. Treatment of HUVECs prevents VEGF-induced generation of reactive oxygen species (ROS) and malondialdehyde (MDA) and also inhibits VEGF-induced NF-κB nuclear translocation as well as DNA-binding activity. The VEGF-induced release of various angiogenic cytokines and chemokines in HUVECs was also significantly blunted by vialinin A. Most importantly, in a mouse model of Matrigel plug assay, vialinin A prevents the formation of new blood vessels and the expression of CD31 and vWF. Thus, our results indicate a novel role of vialinin A in the prevention of neovascularization and suggest that anticancer effects of vialinin A could be mediated through its potent antioxidant and antiangiogenic properties.

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