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 ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 1896-1902 ◽  
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.

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

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.

scholarly journals β-Carotene and angiogenesis

2006 ◽  
Vol 78 (8) ◽  
pp. 1519-1537 ◽  
Author(s):  
Aldona Dembińska-Kieć ◽  
Malgorzata Malczewska-Malec ◽  
Anna Polus ◽  
Beata Kieć-Wilk ◽  
Joanna Grzybowska ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Cell Function ◽  
Cell Types ◽  
Cellular Migration ◽  
Detectable Effect ◽  
Endothelial Cell Function ◽  
Expression Of Genes ◽  
Β Carotene

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.

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

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.

A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase

1994 ◽  
Vol 14 (1) ◽  
pp. 509-517
Author(s):  
W Li ◽  
R Nishimura ◽  
A Kashishian ◽  
A G Batzer ◽  
W J Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Intracellular Signaling ◽  
Egf Receptor ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptors ◽  
Ras Signaling ◽  
Pdgf Receptor ◽  
Phosphotyrosine Phosphatase ◽  
Src Homology

Autophosphorylated growth factor receptors provide binding sites for the src homology 2 domains of intracellular signaling molecules. In response to epidermal growth factor (EGF), the activated EGF receptor binds to a complex containing the signaling protein GRB2 and the Ras guanine nucleotide-releasing factor Sos, leading to activation of the Ras signaling pathway. We have investigated whether the platelet-derived growth factor (PDGF) receptor binds GRB2-Sos. In contrast with the EGF receptor, the GRB2 does not bind to the PDGF receptor directly. Instead, PDGF stimulation induces the formation of a complex containing GRB2; 70-, 80-, and 110-kDa tyrosine-phosphorylated proteins; and the PDGF receptor. Moreover, GRB2 binds directly to the 70-kDa protein but not to the PDGF receptor. Using a panel of PDGF beta-receptor mutants with altered tyrosine phosphorylation sites, we identified Tyr-1009 in the PDGF receptor as required for GRB2 binding. Binding is inhibited by a phosphopeptide containing a YXNX motif. The protein tyrosine phosphatase Syp/PTP1D/SHPTP2/PTP2C is approximately 70 kDa, binds to the PDGF receptor via Tyr-1009, and contains several YXNX sequences. We found that the 70-kDa protein that binds to the PDGF receptor and to GRB2 comigrates with Syp and is recognized by anti-Syp antibodies. Furthermore, both GRB2 and Sos coimmunoprecipitate with Syp from lysates of PDGF-stimulated cells, and GRB2 binds directly to tyrosine-phosphorylated Syp in vitro. These results indicate that GRB2 interacts with different growth factor receptors by different mechanisms and the cytoplasmic phosphotyrosine phosphatase Syp acts as an adapter between the PDGF receptor and the GRB2-Sos complex.

scholarly journals Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 931-939 ◽  
Author(s):  
Cassin Kimmel Williams ◽  
Ji-Liang Li ◽  
Matilde Murga ◽  
Adrian L. Harris ◽  
Giovanna Tosato
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Function ◽  
Umbilical Vein ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Endothelial Cell Function ◽  
Notch Ligand ◽  
Neuropilin 1 ◽  
Umbilical Vein Endothelial Cells

AbstractDelta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing endothelium and in some tumor endothelium, and it is induced by vascular endothelial growth factor (VEGF)-A and hypoxia. Gene targeting studies have shown that Dll4 is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are currently not defined. In this study, we generated primary human endothelial cells that overexpress Dll4 protein to study Dll4 function and mechanism of action. Human umbilical vein endothelial cells retrovirally transduced with Dll4 displayed reduced proliferative and migratory responses selectively to VEGF-A. Expression of VEGF receptor-2, the principal signaling receptor for VEGF-A in endothelial cells, and coreceptor neuropilin-1 was significantly decreased in Dll4-transduced endothelial cells. Consistent with Dll4 signaling through Notch, expression of HEY2, one of the transcription factors that mediates Notch function, was significantly induced in Dll4-overexpressing endothelial cells. The γ-secretase inhibitor L-685458 significantly reconstituted endothelial cell proliferation inhibited by immobilized extracellular Dll4 and reconstituted VEGFR2 expression in Dll4-overerexpressing endothelial cells. These results identify the Notch ligand Dll4 as a selective inhibitor of VEGF-A biologic activities down-regulating 2 VEGF receptors expressed on endothelial cells and raise the possibility that Dll4 may be exploited therapeutically to modulate angiogenesis.

Akt-1 Regulates Angiogenesis in Skin.

Blood ◽  
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.

I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4039-4045
Author(s):  
Giovanni Bernardini ◽  
Gaia Spinetti ◽  
Domenico Ribatti ◽  
Grazia Camarda ◽  
Lucia Morbidelli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Rnase Protection Assay ◽  
Chorioallantoic Membrane ◽  
Rnase Protection ◽  
Cc Chemokine ◽  
Cell Functions

Several chemokines have been shown to act as angiogenic molecules or to modulate the activity of growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor (VEGF). The detection of the CC chemokine receptor (CCR) 8 message in human umbilical vein endothelial cells (HUVECs) by reverse transcription– polymerase chain reaction (RT-PCR) and RNase protection assay (RPA), prompted us to investigate the potential role exerted by the CC chemokine I-309, a known ligand of such receptor, in both in vitro and in vivo angiogenesis assays. We show here that I-309 binds to endothelial cells, stimulates chemotaxis and invasion of these cells, and enhances HUVEC differentiation into capillary-like structures in an in vitro Matrigel assay. Furthermore, I-309 is an inducer of angiogenesis in vivo in both the rabbit cornea and the chick chorioallantoic membrane assay (CAM).

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

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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