β-Carotene and angiogenesis

Carotenoids and retinoids modulate growth and differentiation of a variety of cell types and are fundamental regulators of development. Endothelial cells play an important role in angiogenesis, which is essential for organogenesis and tissue remodeling, but also inflammatory response or carcinogenesis. Binding to the retinoid (RARs) or rexinoid (RXRs) receptors, all-trans-RA, 13-cis-RA, 9-cis-RA, and synthetic retinoids and rexinoids showed antiangiogenic properties in several models. However, the role of β-carotene in endothelial cell function and angiogenesis is still poorly characterized. Although in our experiments, β-carotene used in nontoxic concentrations (up to 3 μM) had no detectable effect on the proliferation or apoptosis of HUVECs or umbilical-cord-blood-derived endothelial progenitors; β-carotene did not change the tubulogenic activity of cells in an in vitro angiogenesis model, but it potently activated the migration of endothelial and progenitor cells. β-Carotene also promoted the development of microcapillaries in a matrigel plug injected subcutaneously into mice. The analysis of microarray data from endothelial cells revealed that β-carotene modified the expression of genes involved in activation of chemotaxis, cell/cell and cell/matrix adhesion, matrix reorganization, G-protein-regulated intracellular signaling as well as genes involved in the rapid remodeling of the actin cytoskeleton. We conclude that physiological levels of β-carotene stimulate early steps of angiogenic activity of endothelial cells by activation of cellular migration as well as matrix reorganization and reduction of cell adhesion.

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Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

Blood ◽

10.1182/blood-2005-04-1524 ◽

2006 ◽

Vol 107 (5) ◽

pp. 1896-1902 ◽

Cited By ~ 32

Author(s):

Debora Faraone ◽

Maria S. Aguzzi ◽

Gianluca Ragone ◽

Katia Russo ◽

Maurizio C. Capogrossi ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Intracellular Signaling ◽

Cell Function ◽

Umbilical Vein ◽

Pdgf Receptor ◽

Inhibitory Effects ◽

Fgf Receptor ◽

Endothelial Cell Function

Previous evidence has shown that platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor-2 (FGF-2) directly interact with high affinity, leading to potent reciprocal inhibitory effects on bovine endothelial cells and rat vascular smooth muscle cells. In this study, we report that PDGF-BB inhibits a series of FGF-2–induced events, such as proliferation of human umbilical vein endothelial cells (HUVECs), FGF-2 cellular internalization, phosphorylation of intracellular signaling factors including p38, rac1/cdc42, MKK4, and MKK3/6, and phosphorylation of FGF-receptor 1 (FGF-R1). PDGF-receptor-α (PDGF-Rα) was found to mediate PDGF-BB inhibitory effects because its neutralization fully restored FGF-2 mitogenic activity and internalization. Additional biochemical analyses, coimmunoprecipitation experiments, and FRET analysis showed that FGF-R1 and PDGF-Rα directly interact in vitro and in vivo and that this interaction is somehow increased in the presence of the corresponding ligands FGF-2 and PDGF-BB. These results suggest that FGF-R1/PDGF-Rα heterodimerization may represent a novel endogenous mechanism to modulate the action of these receptors and their ligands and to control endothelial cell function.

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The Cytoplasmic Actins in the Regulation of Endothelial Cell Function

International Journal of Molecular Sciences ◽

10.3390/ijms22157836 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7836

Author(s):

Vera B. Dugina ◽

Galina S. Shagieva ◽

Anton S. Shakhov ◽

Irina B. Alieva

Keyword(s):

Endothelial Cells ◽

Actin Cytoskeleton ◽

Spatial Organization ◽

Cell Function ◽

Cell Types ◽

Structural Basis ◽

Endothelial Cell Function ◽

Vascular Walls

The primary function of the endothelial cells (EC) lining the inner surface of all vessels is to regulate permeability of vascular walls and to control exchange between circulating blood and tissue fluids of organs. The EC actin cytoskeleton plays a crucial role in maintaining endothelial barrier function. Actin cytoskeleton reorganization result in EC contraction and provides a structural basis for the increase in vascular permeability, which is typical for many diseases. Actin cytoskeleton in non-muscle cells presented two actin isoforms: non-muscle β-cytoplasmic and γ-cytoplasmic actins (β-actins and γ-actins), which are encoded by ACTB and ACTG1 genes, respectively. They are ubiquitously expressed in the different cells in vivo and in vitro and the β/γ-actin ratio depends on the cell type. Both cytoplasmic actins are essential for cell survival, but they perform various functions in the interphase and cell division and play different roles in neoplastic transformation. In this review, we briefly summarize the research results of recent years and consider the features of the cytoplasmic actins: The spatial organization in close connection with their functional activity in different cell types by focusing on endothelial cells.

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Investigation of Wall Shear Stress in Cardiovascular Research and in Clinical Practice—From Bench to Bedside

International Journal of Molecular Sciences ◽

10.3390/ijms22115635 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5635

Author(s):

Katharina Urschel ◽

Miyuki Tauchi ◽

Stephan Achenbach ◽

Barbara Dietel

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Wall Shear Stress ◽

Cell Function ◽

Computational Techniques ◽

Apical Surface ◽

Cardiovascular Research ◽

Endothelial Cell Function ◽

Wall Shear

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as “wall shear stress (WSS)”, and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.

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Abstract 101: MiR-4260 Promotes the Proliferation, Migration, and Tube Formation of Human Umbilical Vein Endothelial Cells

Circulation Research ◽

10.1161/res.117.suppl_1.101 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Qi Sun ◽

Dongcao Lv ◽

Qiulian Zhou ◽

Yihua Bei ◽

Junjie Xiao

Keyword(s):

Endothelial Cells ◽

Target Genes ◽

Cell Function ◽

Umbilical Vein ◽

Tube Formation ◽

Endothelial Cell Function ◽

Human Umbilical Vein ◽

And Migration ◽

Umbilical Vein Endothelial Cells

MicroRNAs (miRNAs, miRs), endogenous small non-coding RNA, have been shown to act as essential regulators in angiogenesis which plays important roles in improving blood flow and cardiac function following myocardial infarction. The current study investigated the potential of miR-4260 in endothelial cell function and angiogenesis using human umbilical vein endothelial cells (HUVEC). Our data demonstrated that overexpression of miR-4260 was associated with increased proliferation and migration of HUVEC using EdU incorporation assay (17.25%±1.31 vs 25.78%±1.24 in nc-mimics vs miR-4260 mimics, respectively) and wound healing assay, respectively. While downregulation of miR-4260 inhibited the proliferation (17.90%±1.37 vs 10.66%±1.41 in nc-inhibitor vs miR-4260 inhibitor, respectively) and migration of HUVEC. Furthermore, we found that miR-4260 mimics increased (129.75±3.68 vs 147±3.13 in nc-mimics vs miR-4260 mimics, respectively), while miR-4260 inhibitor decreased the tube formation of HUVECs in vitro (123.25±2.17 vs 92±4.45 in nc-inhibitor vs miR-4260 inhibitor expression, respectively). Our data indicate that miR-4260 contributes to the proliferation, migration and tube formation of endothelial cells, and might be essential regulators for angiogenesis. Further study is needed to investigate the underlying mechanism that mediates the role of miR-4260 in angiogenesis by identifying its putative downstream target genes.

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Akt-1 Regulates Angiogenesis in Skin.

Blood ◽

10.1182/blood.v104.11.845.845 ◽

2004 ◽

Vol 104 (11) ◽

pp. 845-845

Author(s):

Tatiana Byzova ◽

Juhua Chen ◽

Payaningal R. Somanath

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Blood Vessels ◽

Cell Function ◽

Active Form ◽

Endothelial Cell Migration ◽

Matrix Composition ◽

Adhesive Properties ◽

Endothelial Cell Function

Abstract The major mechanism to adapt to ischemic conditions is the development of neovascularization, i.e. angiogenesis, a process driven by members of VEGF family of growth factors. Phosphoinositide 3-kinase/Akt pathway is a critical component of the signaling network that regulates endothelial cell function related to angiogenesis. VEGF treatment of endothelial cells results in rapid phosphorylation of Akt. Our studies demonstrated that Akt kinase activity is necessary for VEGF-induced and integrin-mediated endothelial cell adhesion and migration. Moreover, cell transfection with a constitutive active form of Akt (myr-Akt) leads to increased function of integrin receptors. Using Akt-1 null mice we found that Akt-1 controls VEGF-induced and integrin-dependent endothelial cell responses in vitro. Impaired endothelial cell migration and adhesion to extracellular matrix and a reduced rate of cell proliferation were observed in Akt-1 (−/−) endothelial cells compared to WT. There are three Akt isoforms with different tissue distribution, however, it appears that Akt-1 is a predominant isoform in skin and in skin microvasculature. This observation prompted us to perform series of in vivo experiments designed to assess the angiogenic response in skin in the absence of Akt-1. Angiogenesis assay using matrigel plugs revealed that the weight and hemoglobin content of matrigel plugs is about two fold higher in Akt (−/−) mice compared to WT mice. Tumor angiogenesis also appears to be enhanced in Akt(−/−) mice, resulting in the significantly lower degree of tumor necrosis. Blood vessels in Akt (−/−) mice appear to be smaller in diameter and have reduced laminin content. Our analysis revealed significant changes in blood vessel wall matrix composition of Akt (−/−) mice as compared to WT animals. These changes resulted in increased vascular permeability in skin of Akt (−/−) mice. Akt-1 is known to target multiple cellular processes including adhesive properties, cell survival, transcription and translation. It appears that the phenotype of Akt-1 (−/−) mice depends on the equilibrium between pro-angiogenic and anti-angiogenic roles of Akt-1 and reveals a central role for Akt-1 in the regulation of matrix production and maturation of blood vessels.

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Comparison of combination treatment with endostatin, soluble neuropilin-1 and thrombospondin-2 to single inhibitors in antiangiogenic therapy of renal cell carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.15648 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 15648-15648

Author(s):

G. Bartsch ◽

K. Eggert ◽

S. Loges ◽

W. Fiedler ◽

E. Laack ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Endothelial Cells ◽

Endothelial Cell ◽

Cell Function ◽

Lung Metastases ◽

Endothelial Cell Function ◽

Tumor Weight ◽

Neuropilin 1 ◽

Angiogenic Inhibitors

15648 Background: Combinations of cytotoxic drugs lead to increased activity and minimize resistance compared to single agents in tumor therapy. Similarly, antiangiogenic treatment could be improved by combinations targeting different pathways. We investigated a combination of endogenous inhibitors using endostatin (ES), soluble Neuropilin-1 (sNP-1), and thrombospondin-2 (TSP-2) in a model of renal cell carcinoma. Methods: Porcine aortic endothelial cells have been engineered for stable production of angiogenic inhibitors by lipofection and were encapsulated in sodium alginate microbeads. Proliferation of human umbilical vein endothelial cells or Renca renal carcinoma cells was examined after incubation with different microbeads. Similarly, effects of inhibitors on endothelial cell function were tested in tube formation and in vitro wound assays. Microbeads were implanted into SCID mice with subcutaneously growing tumors derived from Renca cells or in mice developing lung metastases after intravenous injection of tumor cells. Results: Factors released from microbeads inhibited endothelial cell function but had no effect on tumor cell proliferation in vitro. In vivo, subcutaneous tumor growth was inhibited similarly by each angiogenic inhibitor alone. After 30 days mean tumor weight was 1.3 g in controls and 0.17, 0.18, 0.18g in ES, sNP-1, and TSP-2 treated mice, respectively. Tumor weight in mice treated with all three inhibitors was further reduced to 0.03g. Histological analyses confirmed antiangiogenic activity by inhibition of microvessel density in treated tumors. In a metastastic model treatment with angiogenic inhibitors induced a significant reduction in size and number of lung metastases with additive effects when factors were used in combination. Conclusions: We conclude that combination therapy targeting multiple angiogenic pathways has synergistic activity and could help to avoid resistance to single inhibitors in tumor treatment. No significant financial relationships to disclose.

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Effects of HIV-1 gp120 and TAT-derived microvesicles on endothelial cell function

Journal of Applied Physiology ◽

10.1152/japplphysiol.01048.2018 ◽

2019 ◽

Vol 126 (5) ◽

pp. 1242-1249

Author(s):

Jamie G. Hijmans ◽

Kelly Stockelman ◽

Ma’ayan Levy ◽

L. Madden Brewster ◽

Tyler D. Bammert ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Endothelial Cell ◽

Viral Protein ◽

Cell Function ◽

Endothelial Damage ◽

Endothelial Cell Function ◽

Gp 120 ◽

Hiv 1

The aims of this study were twofold. The first was to determine if human immunodeficiency virus (HIV)-1 glycoprotein (gp) 120 and transactivator of transcription (Tat) stimulate the release of endothelial microvesicles (EMVs). The second was to determine whether viral protein-induced EMVs are deleterious to endothelial cell function (inducing endothelial cell inflammation, oxidative stress, senescence and increasing apoptotic susceptibility). Human aortic endothelial cells (HAECs) were treated with recombinant HIV-1 proteins Bal gp120 (R5), Lav gp120 (X4), or Tat. EMVs released in response to each viral protein were isolated and quantified. Fresh HAECs were treated with EMVs generated under control conditions and from each of the viral protein conditions for 24 h. EMV release was higher ( P < 0.05) in HAECs treated with R5 (141 ± 21 MV/µl),X4 (132 ± 20 MV/µl), and Tat (130 ± 20 MV/µl) compared with control (61 ± 13 MV/µl). Viral protein EMVs induced significantly higher endothelial cell release of proinflammatory cytokines and expression of cell adhesion molecules than control. Reactive oxygen species production was more pronounced ( P < 0.05) in the R5-, X4- and Tat-EMV-treated cells. In addition, viral protein-stimulated EMVs significantly augmented endothelial cell senescence and apoptotic susceptibility. Concomitant with these functional changes, viral protein-stimulated EMVs disrupted cell expression of micro-RNAs 34a, 126, 146a, 181b, 221, and miR-Let-7a ( P < 0.05). These results demonstrate that HIV-1 gp120 and Tat stimulate microvesicle release from endothelial cells, and these microvesicles confer pathological effects on endothelial cells by inducing inflammation, oxidative stress, and senescence as well as enhancing susceptibility to apoptosis. Viral protein-generated EMVs may contribute to the increased risk of vascular disease in patients with HIV-1.NEW & NOTEWORTHY Human immunodeficiency virus (HIV)-1-related proteins glycoprotein (gp) 120 and transactivator of transcription (Tat)-mediated endothelial damage and dysfunction are poorly understood. Endothelial microvesicles (EMVs) serve as indicators and potent mediators of endothelial dysfunction. In the present study we determined if HIV-1 R5- and X4-tropic gp120 and Tat stimulate EMV release in vitro and if viral protein-induced EMVs are deleterious to endothelial cell function. gp120 and Tat induced a marked increase in EMV release. Viral protein-induced EMVs significantly increased endothelial cell inflammation, oxidative stress, senescence, and apoptotic susceptibility in vitro. gp120- and Tat-derived EMVs promote a proinflammatory, pro-oxidative, prosenescent, and proapoptotic endothelial phenotype and may contribute to the endothelial damage and dysfunction associated with gp120 and Tat.

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Isolation, culture, and characterization of rat lung microvascular endothelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.267.4.l433 ◽

1994 ◽

Vol 267 (4) ◽

pp. L433-L441 ◽

Cited By ~ 14

Author(s):

J. C. Magee ◽

A. E. Stone ◽

K. T. Oldham ◽

K. S. Guice

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cell Function ◽

Primary Cultures ◽

Microvascular Endothelial Cells ◽

Rat Lung ◽

Simple Method ◽

Endothelial Cell Function ◽

Microvascular Endothelial

Highly pure primary cultures of rat lung microvascular endothelial cells were obtained from peripheral lung tissue using a combination of selective culture strategies. The cells had a characteristic morphology consistent with an endothelial origin and were positive for a number of endothelial cell markers, including uptake of fluorescent acetylated lactate dehydrogenase, binding of the lectin Bandeiraea simplicifolia I, and positive immunofluorescence staining with two endothelial cell monoclonal antibodies. The cells behaved as microvascular endothelial cells using an in vitro angiogenesis assay. This isolation method provides a simple method for culturing the pulmonary microvasculature of the rat and these studies support the idea that endothelial cells from different vessels exhibit phenotypic heterogeneity. This method should prove useful for studying specialized endothelial cell function and differentiation in vitro.

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Nanotechnology for Treating Damaged Organs

Solid State Phenomena ◽

10.4028/www.scientific.net/ssp.140.119 ◽

2008 ◽

Vol 140 ◽

pp. 119-126

Author(s):

Jing Lu ◽

Thomas J. Webster

Keyword(s):

Endothelial Cells ◽

Cell Function ◽

In Vitro Study ◽

The Body ◽

Vitro Study ◽

Nanostructured Surface ◽

Vascular Stent ◽

Endothelial Cell Function ◽

Vascular Stents

Atherosclerosis, which is caused by endothelial dysfunction, vascular inflammation, and the build-up of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall, is one of the most important complications of health. Vascular stenting is the procedure of implanting a thin tube into the site of a narrow or blocked artery due to atherosclerosis. However, the application of vascular stents using conventional metals is limited because the implantation process will cause significant injury to the vascular wall and endothelium, which functions as a protective biocompatible barrier between the tissue and the circulating blood, resulting in neointima hyperplasia followed by the development of long-term restenosis. The objective of this in vitro study was to investigate the endothelial cell function, especially their adhesion behaviour, on highly controllable features on nanostructured surface. Considering the importance of the endothelium and its properties, highly controllable nanostructured surface features of titanium, a popular vascular stent metal, were created using E-beam evaporation to promote endothelialization and to control the direction of endothelial cells on vascular stents. Endothelial cells are naturally aligned with the blood flow in the body. In this manner, the present in vitro study provides much promise for the use of nanotechnology for improving metallic materials for vascular stent applications.

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The CXCL2/IL8/CXCR2 Pathway Is Relevant for Brain Tumor Malignancy and Endothelial Cell Function

International Journal of Molecular Sciences ◽

10.3390/ijms22052634 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2634

Author(s):

Ruth Urbantat ◽

Anne Blank ◽

Irina Kremenetskaia ◽

Peter Vajkoczy ◽

Güliz Acker ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Function ◽

The Cancer Genome Atlas ◽

Human Endothelial Cells ◽

In Vitro Proliferation ◽

Endothelial Cell Function ◽

Human Gbm ◽

And Migration ◽

The Impact

We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 effecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma.

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