Induction of nitric oxide by erythropoietin is mediated by the β common receptor and requires interaction with VEGF receptor 2

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 896-905 ◽  
Author(s):  
Larysa Sautina ◽  
Yuri Sautin ◽  
Elaine Beem ◽  
Zhuo Zhou ◽  
Anna Schuler ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Common Receptor ◽  
The Common ◽  
Β Receptor ◽  
And Performance ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) have profound effects on the endothelium and endothelial progenitor cells (EPCs), which originate from the bone marrow and differentiate into endothelial cells. Both EPO and VEGF have demonstrated an ability to increase the number and performance properties of EPCs. EPC behavior is highly dependent on nitric oxide (NO), and both VEGF and EPO can stimulate intracellular NO. EPO can bind to the homodimeric EPO receptor (EPO-R) and the heterodimeric receptor, EPO-R and the common β receptor (βC-R). Although VEGF has several receptors, VEGF-R2 appears most critical to EPC function. We demonstrate that EPO induction of NO is dependent on the βC-R and VEGF-R2, that VEGF induction of NO is dependent on the expression of the βC-R, and that the βC-R and VEGF-R2 interact. This is the first definitive functional and structural evidence of an interaction between the 2 receptors and has implications for the side effects of EPO.

The Production of Vascular Endothelial Growth Factor Is Decreased in Acute Myelogenous Leukemia Cases That Are Treated with Chemotherapeutic Agents and Show the Prolonged Bone Marrow Suppression.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4313-4313
Author(s):  
Haruko Tashiro ◽  
Mitsuho Noguchi ◽  
Ryosuke Shirasaki ◽  
Kazuo Kawasugi ◽  
Naoki Shirafuji
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Bone Marrow Cells ◽  
Bone Marrow Suppression ◽  
Myelogenous Leukemia ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Acute Myelogenous ◽  
Endothelial Growth Factor ◽  
Marrow Cells

Abstract Objective: There have been reported that the levels of serum vascular endothelial growth factor (VEGF) were decreased in aplastic anemia cases. We investigated VEGF system after chemotherapy to acute myelogenous leukemia (AML) cases, and determined whether VEGF system influenced the prolonged bone marrow suppression in these cases. Materials and Methods: Sera and bone marrow cells were prepared from 30 AML cases including 10 cases of AML (M3) at the onset of the disease, after chemotherapy, and the recovery periods, and the concentration of VEGF in sera of the patients and in the conditioned media obtained from bone marrow-cell cultures was measured with ELISA kit (Quantikine; R&D Systems). The expression of VEGF, VEGF receptor type-1 and VEGF receptor type-2 was analyzed with RT-PCR. The biological effect of VEGF on the bone marrow cells which showed the prolonged suppression after chemotherapy was assayed with colony-formation with or without any cytokines. Result and Discussion: As was reported previously, VEGF levels were significantly increased in M3 cases. In other types of AML cases the levels of VEGF production varied. When patients were given chemotherapy and the bone marrow suppression was prolonged, the production levels of VEGF were significantly diminished less than that observed in AML cases with normal bone marrow recovery. In M3 cases that were treated with all-trans retinoic acid and the prolonged bone marrow-suppression was observed, VEGF production was also suppressed. The expression of VEGFR-1 and -2 was observed in bone marrow cells from prolonged bone marrow suppression cases. In these cases, when bone marrow cells were cultured with VEGF, synergistic effects with G-CSF and EPO were observed with colony-formation assay. These observations indicate that VEGF works on the important role for the hematopoietic recovery after chemotherapy in AML cases.

scholarly journals Vasoactive and Permeability Effects of Vascular Endothelial Growth Factor-165 in the Term in Vitro Dually Perfused Human Placental Lobule

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4734-4744 ◽  
Author(s):  
P. Brownbill ◽  
G. C. McKeeman ◽  
J. C. Brockelsby ◽  
I. P. Crocker ◽  
C. P. Sibley
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Culture Techniques ◽  
Vasodilatory Effect ◽  
Endothelial Growth Factor ◽  
Maternal Side

Vascular endothelial growth factor (VEGF) is an important vasodilator and effector of permeability in systemic blood vessels. Molecular and tissue culture techniques have provided evidence for its placental synthesis and release. Using an in vitro dual-perfusion model of the term placental lobule from normal pregnancy, we report here the relative secretion of total VEGF, soluble VEGF receptor (VEGFR)-1, and free VEGF into the maternal and fetoplacental circulations of the placenta. We tested the hypothesis that VEGF has vasomotor and permeability effects in the fetoplacental circulation of the human placenta, and we examined the broad intracellular pathways involved in the vasodilatory effect that we found. We show that total VEGF is released into the fetal and maternal circulations in a bipolar fashion, with a bias toward maternal side output. Soluble VEGFR-1 was also secreted into both circulations with bias toward the maternal side. Consequently, free VEGF (12.8 ± 2.4 pg/ml, mean ± se) was found only in the fetoplacental circulation. VEGF-165 was found to be a potent vasodilator of the fetoplacental circulation (maximum response: 77% of previous steady-state fetal-side inflow hydrostatic pressure after preconstriction with U46619; EC50 = 71 pm). This vasodilatory effect was mediated by the VEGFR-2 receptor and nitric oxide in a manner-independent of the involvement of prostacyclin and the src-family tyrosine kinases. However, nitric oxide could explain only 50% of the vasodilatory effect. Finally, we measured the permeability of the perfused placenta to inert hydrophilic tracers and found no difference in the presence and absence of VEGF.

Aspirin inhibits endothelial nitric oxide synthase (eNOS) and Flk-1 (vascular endothelial growth factor receptor-2) prior to rat colon tumour development

2004 ◽  
Vol 106 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Marta ESCRIBANO ◽  
Laura MOLERO ◽  
Antonio LÓPEZ-FARRÉ ◽  
Cynthia ABARRATEGUI ◽  
Carolina CARRASCO ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Blood Vessels ◽  
Caspase 3 ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Colonic Tissue ◽  
Colon Tumour ◽  
Endothelial Growth Factor

Formation of blood vessels is a fundamental element in the control of tumour growth in which vascular endothelial growth factor (VEGF) and nitric oxide (NO) have been demonstrated to be involved. Our aim was to analyse whether changes in the expression of endothelial NO synthase (eNOS) and VEGF in colonic tissue could be detected early and even before the identification of colon tumour-associated morphological modifications in azoxymethane-treated rats. We studied further whether aspirin treatment changed these parameters. An increased expression of both eNOS and VEGF in colonic tissue from azoxymethane-treated rats compared with that from control rats was found. Aspirin treatment (10 mg/kg of body weight per day) reduced eNOS expression, but failed to modify the expression of VEGF in the colonic tissue of azoxymethane-treated rats. No evidence of aberrant crypt formation or changes in the number of blood vessels were observed in the colon of any of the animals studied. Expression of the VEGF receptor Flk-1, but not Flt-1, was increased in colonic tissue of azoxymethane-treated rats compared with control rats. The expression of Flk-1 was mainly localized in the epithelial cells, particularly in the lower part of the crypt. Aspirin treatment reduced Flk-1 expression in both control and azoxymethane-treated rats. Caspase-3 activity, which has been considered as an apoptotic index, was almost undetectable in azoxymethane-treated rats. Aspirin treatment stimulated caspase-3 activity. Overexpression of eNOS, VEGF and its receptor Flk-1 occurred early after azoxymethane administration in rat colonic tissue, even before morphological changes associated with tumour generation were observed, and aspirin prevented the overexpression of both eNOS and VEGF receptor Flk-1.

Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 1849-1856 ◽  
Author(s):  
Masato Murakami ◽  
Shinobu Iwai ◽  
Sachie Hiratsuka ◽  
Mai Yamauchi ◽  
Kazuhide Nakamura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Bone Destruction ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Human T Cell ◽  
Endothelial Growth Factor

AbstractVascular endothelial growth factor (VEGF) and VEGF receptor-1 (VEGFR-1/Flt-1) were shown to be involved in pathological angiogenesis, particularly rheumatoid arthritis (RA). However, the molecular basis of their actions is not fully understood. Here we report that in a murine model of RA, deletion of the tyrosine kinase (TK) domain of VEGFR-1 decreased the incidence and clinical symptoms of RA. Pathological symptoms, such as synovial hyperplasia, inflammatory infiltrates, pannus formation, and cartilage/bone destruction, became milder in Vegfr-1 tk–/– mice compared with wild-type (Wt) mice in the human T-cell leukemia virus-1 (HTLV-1) pX–induced chronic models. VEGFR-1 TK-deficient bone marrow cells showed a suppression of multilineage colony formation. Furthermore, macrophages induced to differentiate in vitro showed a decrease in immunologic reactions such as phagocytosis and the secretion of interleukin-6 (IL-6) and VEGF-A. Treatment of this RA model with a small molecule inhibitor for VEGFR TK, KRN951, also attenuated the arthritis. These results indicate that the VEGFR-1 TK signaling modulates the proliferation of bone marrow hematopoietic cells and immunity of monocytes/macrophages and promotes chronic inflammation, which may be a new target in the treatment of RA.

scholarly journals Lipid Raft Association Stabilizes VEGF Receptor 2 in Endothelial Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 798
Author(s):  
Ibukunoluwapo O. Zabroski ◽  
Matthew A. Nugent
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Lipid Rafts ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Potential Mechanism ◽  
Lysosomal Degradation ◽  
Extracellular Signal ◽  
The Stability ◽  
Endothelial Growth Factor

The binding of vascular endothelial growth factor A (VEGF) to VEGF receptor-2 (VEGFR-2) stimulates angiogenic signaling. Lipid rafts are cholesterol-dense regions of the plasma membrane that serve as an organizational platform for biomolecules. Although VEGFR2 has been shown to colocalize with lipid rafts to regulate its activation, the effect of lipid rafts on non-activated VEGFR2 has not been explored. Here, we characterized the involvement of lipid rafts in modulating the stability of non-activated VEGFR2 in endothelial cells using raft disrupting agents: methyl-β-cyclodextrin, sphingomyelinase and simvastatin. Disrupting lipid rafts selectively decreased the levels of non-activated VEGFR2 as a result of increased lysosomal degradation. The decreased expression of VEGFR2 translated to reduced VEGF-activation of the extracellular signal-regulated protein kinases (ERK). Overall, our results indicate that lipid rafts stabilize VEGFR2 and its associated signal transduction activities required for angiogenesis. Thus, modulation of lipid rafts may provide a means to regulate the sensitivity of endothelial cells to VEGF stimulation. Indeed, the ability of simvastatin to down regulate VEGFR2 and inhibit VEGF activity suggest a potential mechanism underlying the observation that this drug improves outcomes in the treatment of certain cancers.

scholarly journals Pro-Angiogenic Effects of Resveratrol in Brain Endothelial Cells: Nitric Oxide-Mediated Regulation of Vascular Endothelial Growth Factor and Metalloproteinases

2012 ◽  
Vol 32 (5) ◽  
pp. 884-895 ◽  
Author(s):  
Fabricio Simão ◽  
Aline S Pagnussat ◽  
Ji Hae Seo ◽  
Deepti Navaratna ◽  
Wendy Leung ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Vascular Endothelial ◽  
Cerebral Endothelial Cells ◽  
Endothelial Growth Factor

Resveratrol may be a powerful way of protecting the brain against a wide variety of stress and injury. Recently, it has been proposed that resveratrol not only reduces brain injury but also promotes recovery after stroke. But the underlying mechanisms are unclear. Here, we tested the hypothesis that resveratrol promotes angiogenesis in cerebral endothelial cells and dissected the signaling pathways involved. Treatment of cerebral endothelial cells with resveratrol promoted proliferation, migration, and tube formation in Matrigel assays. Consistent with these pro-angiogenic responses, resveratrol altered endothelial morphology resulting in cytoskeletal rearrangements of β-catenin and VE-cadherin. These effects of resveratrol were accompanied by activation of phosphoinositide 3 kinase (PI3-K)/Akt and Mitogen-Activated Protein Kinase (MAPK)/ERK signaling pathways that led to endothelial nitric oxide synthase upregulation and increased nitric oxide (NO) levels. Subsequently, elevated NO signaling increased vascular endothelial growth factor and matrix metalloproteinase levels. Sequential blockade of these signaling steps prevented resveratrol-induced angiogenesis in cerebral endothelial cells. These findings provide a mechanistic basis for the potential use of resveratrol as a candidate therapy to promote angiogenesis and neurovascular recovery after stroke.

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